Journal articles on the topic 'Substance P; cerebral edema; rats'
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Levasseur, Joseph E., John L. Patterson, Claudia I. Garcia, Michael A. Moskowitz, Sung C. Choi, and Hermes A. Kontos. "Effect of neonatal capsaicin treatment on neurogenic pulmonary edema from fluid-percussion brain injury in the adult rat." Journal of Neurosurgery 78, no. 4 (April 1993): 610–18. http://dx.doi.org/10.3171/jns.1993.78.4.0610.
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✓ The frequent occurrence of acute death from pulmonary failure in experimental head injury studies on Sprague-Dawley rats prompted an investigation into the manner in which acute neurogenic pulmonary edema develops in these animals as a result of an applied fluid pressure pulse to the cerebral hemispheres. Studies were performed in adult animals using histamine H1 and H2 blocking agents, or in adult animals treated as neonates with capsaicin to destroy unmyelinated C-fibers. Recordings were made of either the pulmonary arterial or the right ventricular pressure, and the left atrial and femoral arterial pressures before, during, and after injury to provide a record of the hemodynamic response throughout the development of neurogenic pulmonary edema. Head injury triggered the almost immediate development of pressure transients with and without neurogenic pulmonary edema. All rats, regardless of treatment, reacted with nearly identical systemic arterial pressure responses; however, the pulmonary responses followed a time course that was independent of systemic arterial pressure changes. Acute neurogenic pulmonary edema was always associated with a substantial increase in pulmonary arterial and left atrial pressures; conversely, pressure increases of similar magnitude were not always associated with edema. Histamine H1 and H2 blockers significantly reduced the pulmonary pressure surges only in rats free of neurogenic pulmonary edema. All capsaicin-treated rats showed suppressed pulmonary pressure responses, normal lung water content, elevated lung surface tension, and significantly reduced levels of immunoreactive substance P in the spinal cord and vagus nerve. While the pressures cannot clarify how edema influences the observed hemodynamics, they do not support the view that edema is the direct consequence of pulmonary hypertension. It is proposed that neurogenic pulmonary edema is a functional disturbance provoked by adverse stimuli from outside the lungs and that in the rat the primary afferent fiber is essential to the production of this entity.
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Yang, Guo-Yuan, A. Lorris Betz, Thomas L. Chenevert, James A. Brunberg, and Julian T. Hoff. "Experimental intracerebral hemorrhage: relationship between brain edema, blood flow, and blood-brain barrier permeability in rats." Journal of Neurosurgery 81, no. 1 (July 1994): 93–102. http://dx.doi.org/10.3171/jns.1994.81.1.0093.
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✓ There have been few investigations of brain edema formation after intracerebral hemorrhage (ICH), despite the fact that mass effect and edema are important clinical complications. The present study was designed to investigate the time course for the formation and resolution of brain edema and to determine how changes in cerebral blood flow (CBF) and blood-brain barrier (BBB) permeability are temporally related to edema formation following ICH. Anesthetized adult rats received a sterile injection of 100 µl of autologous blood into the caudate nucleus. Water and ion contents were measured immediately, at 4 and 12 hours, and daily to Day 7 (10 time points, six rats at each time) after experimental ICH. The water content of the ipsilateral basal ganglia increased progressively (p < 0.002) over the first 24 hours, then remained constant until after Day 5, when the edema began to resolve. Edema was most severe in the tissue immediately surrounding the hemorrhage; however, it was also present in the ipsilateral cortex, the contralateral cortex, and the basal ganglia. Measurements of local CBF (using [14C]-iodoantipyrine) and BBB permeability (using [3H]-α-aminoisobutyric acid) were obtained in separate groups of six to eight rats at various time intervals between 1 and 48 hours after ICH. Cerebral blood flow was reduced to 50% of control at 1 hour, returned to control values by 4 hours, but then decreased to less than 50% of control between 24 and 48 hours after ICH. The BBB permeability increased significantly prior to the occurrence of significant edema in the tissue surrounding the clot. However, BBB permeability in the more distant structures remained normal despite the development of edema. These results demonstrate a time course for the formation and resolution of brain edema following ICH similar to that observed during focal ischemia. Brain edema forms in the immediate vicinity of the clot as a result of both BBB disruption and the local generation of osmotically active substances and then spreads to adjacent structures. While local ischemia, due to the mass effect of the hemorrhage, may play a role in producing cytotoxic and vasogenic edema, the release of toxic substances from the clot should also be considered. Since edema is nearly maximal by 24 hours after ICH, therapy directed at reducing edema formation must be instituted within the 1st day.
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Stroemer, R. Paul, and Nancy J. Rothwell. "Cortical Protection by Localized Striatal Injection of IL-1ra Following Cerebral Ischemia in the Rat." Journal of Cerebral Blood Flow & Metabolism 17, no. 6 (June 1997): 597–604. http://dx.doi.org/10.1097/00004647-199706000-00001.
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Interleukin-1 (IL-1) receptor antagonist (IL-1ra) markedly reduces infarct volume induced by middle cerebral artery occlusion (MCAO) in the rat, when injected either centrally (intracerebroventricularly) or peripherally. The site or sites of action of IL-1 in stroke pathology, however, are not known. The present study investigated the site(s) of action of IL-1/IL-1ra in ischemic brain damage by studying the effects of local injection of IL-1ra into the cortex or striatum following permanent MCAO in the rat. Cortical injection of IL-1ra (5 µg) did not affect infarct volume in the cortex or striatum measured 24 h after MCAO. In contrast, striatal injection of IL-1ra ipsilateral to the infarction caused a significant and highly reproducible reduction of cortical (37%, p < 0.001) and striatal damage (27%, p < 0.001, corrected for edema) compared with vehicle-injected animals. Injection of IL-1ra (5 µg) into the striatum, contralateral to the infarction, resulted in a small (9%) but significant (p < 0.001) reduction of ipsilateral cortical damage, with no effect on ipsilateral striatal damage. Injection of a higher dose of IL-1ra (7.5 µg) in the contralateral striatum caused a further inhibition of ipsilateral cortical damage (24%, p < 0.001) and a significant reduction of ipsilateral striatal damage (16%, p < 0.001). In separate groups of rats, it was established that core temperature (measured continuously in free-moving animals with remote radiotelemetry) was not affected by striatal or cortical injection of IL-1ra. These data show that injection of IL-1ra into the striatum but not the cortex reduces infarct volume in both the striatum and the cortex, independently of effects on core temperature. These results imply that blocking striatal IL-1 contributes to IL-1ra-protective effects. We hypothesize that IL-1 may influence striatal distal cortical damage through either the release of specific substances or activation of polysynaptic pathways.
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Song, Jiali, Rongqing Chen, Lin Yang, Ge Zhang, Weichen Li, Zhanqi Zhao, Canhua Xu, Xiuzhen Dong, and Feng Fu. "Electrical Impedance Changes at Different Phases of Cerebral Edema in Rats with Ischemic Brain Injury." BioMed Research International 2018 (June 4, 2018): 1–10. http://dx.doi.org/10.1155/2018/9765174.
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Cerebral edema contributes significantly to the morbidity and mortality associated with many common neurologic conditions. Clinically, a diagnostic tool that can be used to monitor cerebral edema in real-time and differentiate between different types of cerebral edema is urgently needed. Because there are differences in electrical impedance between normal cortical tissue and cerebral edema tissue, electrical impedance tomography (EIT) can potentially be used to detect cerebral edema. Accurate recording of the electrical impedance properties of cerebral edema tissue at different time points is important when detecting cerebral edema with EIT. In this study, a rat cerebral edema model was established; then, following the onset of ischemic brain injury, variation in the electrical impedance of cerebral edema was measured at different time points within a 24-hour period and the corresponding morphologic variation was analyzed. After the first six hours, following the onset of ischemic brain injury, the resistivity of brain tissue increased (p < 0.05); during this period, brain cell volume increased (p < 0.05) and the intercellular space decreased (p < 0.05) (behaving like cytotoxic cerebral edema). From 6 to 24 hours, the resistivity of brain tissue decreased; during this time, brain cell volume unchanged (p > 0.05) while intercellular space increased (p < 0.05) (behaving like vasogenic cerebral edema). These findings support the notion that EIT can be used to monitor the development of cerebral edema in real-time and differentiate between different types of brain edema.
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Donkin, James J., Alan J. Nimmo, Ibolja Cernak, Peter C. Blumbergs, and Robert Vink. "Substance P is Associated with the Development of Brain Edema and Functional Deficits after Traumatic Brain Injury." Journal of Cerebral Blood Flow & Metabolism 29, no. 8 (May 13, 2009): 1388–98. http://dx.doi.org/10.1038/jcbfm.2009.63.
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Brain edema and swelling is a critical factor in the high mortality and morbidity associated with traumatic brain injury (TBI). Despite this, the mechanisms associated with its development are poorly understood and interventions have not changed in over 30 years. Although neuropeptides and neurogenic inflammation have been implicated in peripheral edema formation, their role in the development of central nervous system edema after brain trauma has not been investigated. This study examines the role of the neuropeptide, substance P (SP), in the development of edema and functional deficits after brain trauma in rats. After severe diffuse TBI in adult male rats, neuronal and perivascular SP immunoreactivity were increased markedly. Perivascular SP colocalized with exogenously administered Evans blue, supporting a role for SP in vascular permeability. Inhibition of SP action by administration of the neurokinin-1 (NIC,) antagonist, N-acetyl-l-tryptophan, at 30 mins after trauma attenuated vascular permeability and edema formation. Administration of the NIC, antagonist also improved both motor and cognitive neurologic outcomes. These findings suggest that SP release is integrally linked to the increased vascular permeability and edema formation after brain trauma, and that treatment with an NIC, receptor antagonist reduces edema and improves neurologic outcome.
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Mansfield, Robert T., Joanne K. Schiding, Ronald L. Hamilton, and Patrick M. Kochanek. "Effects of Hypothermia on Traumatic Brain Injury in Immature Rats." Journal of Cerebral Blood Flow & Metabolism 16, no. 2 (March 1996): 244–52. http://dx.doi.org/10.1097/00004647-199603000-00009.
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Hypothermia is beneficial in adult models of traumatic brain injury (TBI), but it has not been evaluated in an immature animal model. We hypothesized that brief hypothermia applied after TBI would reduce cerebral edema and lesion volume in immature rats. Male Wistar rats (3–4 weeks of age, 90–140 g) were anesthetized, intubated, mechanically ventilated, and subjected to TBI by a weight drop onto the exposed right parietal cortex. Hypothermic rats were then cooled to a brain temperature of 32.0 ± 0.5°C for 4 h, and control rats were maintained at a brain temperature of 37.0 ± 0.5°C. Cerebral edema (wet — dry weight method) was assessed at 4 and 24 h, and lesion volume was assessed at 5 days. At 4 h, a reduction of percent brain water in the traumatized hemisphere was observed in hypothermic versus normothermic rats (81.75 ± 0.60 vs. 82.53 ± 0.67%; p < 0.05), but by 24 h posttrauma, the groups were similar (p = 0.82). Total lesion volume (47.2 ± 8.5 vs. 44.4 ± 10.0 mm3; p = 0.51) and necrotic volume (20.2 ± 6.3 vs. 20.0 ± 7.9 mm3; p = 0.95) were similar in the hypothermic and normothermic groups. We conclude that in this model, a transient (4-h) application of moderate (32°C) hypothermia reduces the cerebral edema characteristically seen in immature rats at 4 h, but this reduction is not sustained at 24 h. Attenuating or delaying the development of cerebral edema could have important therapeutic relevance after TBI. Transient hypothermia, however, did not reduce lesion volume at 5 days posttrauma.
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Kollmar, Rainer, Thomas Frietsch, Dimitrios Georgiadis, Wolf-Rüdiger Schäbitz, Klaus F. Waschke, Wolfgang Kuschinsky, and Stefan Schwab. "Early Effects of Acid-Base Management during Hypothermia on Cerebral Infarct Volume, Edema, and Cerebral Blood Flow in Acute Focal Cerebral Ischemia in Rats." Anesthesiology 97, no. 4 (October 1, 2002): 868–74. http://dx.doi.org/10.1097/00000542-200210000-00018.
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Background Although the frequency for the use of moderate hypothermia in acute ischemic stroke is increasing, the optimal acid-base management during hypothermia remains unclear. This study investigates the effect of pH- and alpha-stat acid-base management on cerebral blood flow (CBF), infarct volume, and cerebral edema in a model of transient focal cerebral ischemia in rats. Methods Twenty Sprague-Dawley rats were subjected to transient middle cerebral artery occlusion (MCAO) for 2 h during normothermic conditions followed by 5 h of reperfusion during hypothermia (33 degrees C). Animals were artificially ventilated with either alpha- (n = 10) or pH-stat management (n = 10). CBF was analyzed 7 h after induction of MCAO by iodo[(14)C]antipyrine autoradiography. Cerebral infarct volume and cerebral edema were measured by high-contrast silver infarct staining (SIS). Results Compared with the alpha-stat regimen, pH-stat management reduced cerebral infarct volume (98.3 +/- 33.2 mm(3) vs. 53.6 +/- 21.6 mm(3); P > or = 0.05 mean +/- SD) and cerebral edema (10.6 +/- 4.0% vs. 3.1 +/- 2.4%; P > or = 0.05). Global CBF during pH-stat management exceeded that of alpha-stat animals (69.5 +/- 12.3 ml x 100 g(-1) x min(-1) vs. 54.7 +/- 13.3 ml x 100 g(-1) x min; P > or = 0.05). The regional CBF of the ischemic hemisphere was 62.1 +/- 11.2 ml x 100 g(-1) x min(-1) in the pH-stat group versus 48.2 +/- 7.2 ml x 100 g(-1) x min(-1) in the alpha-stat group ( P> or = 0.05). Conclusions In the very early reperfusion period (5 h), pH-stat management significantly decreases cerebral infarct volume and edema as compared with alpha-stat during moderate hypothermia, probably by increasing CBF.
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Sohn, Youngjoo, Ho Chang Kang, Kon Sik Kim, Sun-Min Park, Nak-Won Sohn, Hyuk-Sang Jung, and Sung-Hoon Kim. "Protective Effects of Natrii Sulfas on Cerebral Focal Ischemia Induced by MCAO in Rats." American Journal of Chinese Medicine 37, no. 02 (January 2009): 273–93. http://dx.doi.org/10.1142/s0192415x09006849.
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This study examined the effect of Natrii sulfas, a treatment for stroke patients suffering constipation in Oriental medicine, on the physiological indices and brain edema of rats. Brain edema was induced by a middle cerebral artery occlusion (MCAO), Natrii sulfas was administered after the MCAO. At 3, 6, 15, 24, and 48 hours after reperfusion, the physiological indices such as the fecal weight, urine volume and water content in the stools were assessed. The edema index was measured 48 hours after reperfusion. At 48 hours, the expressions of iNOS, MMP9, VEGF, GFAP, Bax, Bcl-2, c-Fos, and HSP72 positive astrocytes were observed on the brain tissues by immunohistochemistry. Natrii sulfas significantly improved the decrease in fecal weight, urine volume and water content in the stool caused by the ischemic insult (p < 0.05) and attenuated the brain edema caused by the ischemia insult (p < 0.05). Natrii sulfas significantly down-regulated iNOS and MMP9 expressions and attenuated the astrocyte swelling due to brain edema in the penumbra of the cerebral cortex of MCAO rats. Natrii sulfas reduced the excess Bax and HSP72 expressions in ischemic brain, which was statistically significant in the penumbra of the cerebral cortex but not in the caudate putamen. These results suggest Natrii sulfas has a protective effect on ischemia-induced brain edema and improves the physiological symptoms.
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Cherpakov, R. A., and O. A. Grebenchikov. "Effect of Lithium Chloride Concentration on Its Neuroprotective Properties in Ischemic Stroke in Rats." General Reanimatology 17, no. 5 (October 23, 2021): 101–10. http://dx.doi.org/10.15360/1813-9779-2021-5-101-110.
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Currently, a number of experimental studies have demonstrated compelling evidence of neuro-, cardio-, and nephroprotective properties of medications containing lithium chloride.Aim of the study. To evaluate the effect of various concentrations of lithium chloride on ischemic stroke volume and perifocal edema in rats after cerebral ischemia.Material and methods. Male mongrel rats weighing 315±13.5 g were used in the study. The focal ischemia model according to Longa et al. was employed. The animals (n=35) were divided into 5 groups: sham-operated, control group (ischemic stroke model with NaCl 0.9% administration) and three groups who received lithium chloride in different concentrations (4.2 mg/kg, 21 mg/kg and 63 mg/kg). Lithium chloride was administered immediately after cessation of middle cerebral artery occlusion and then every 24 h until euthanasia. To assess the degree of brain damage, the animals underwent magnetic resonance imaging (MRI) on day 2, and brain sections stained with 2,3,5-triphenyltetrazolium chloride were evaluated after euthanasia on day 7. Intergroup differences were assessed using the Mann-Whitney criterion.Results. According to MRI data, lithium chloride at a dose of 4.2 mg/kg had no significant effect on ischemic stroke volume and perifocal edema versus the control group on day 2 (P=0.9). With lithium chloride at 21 mg/kg, stroke volume and perifocal edema were significantly lower than in the control group (by 25%, P=0.04 and 18%, P=0.03, respectively). Lithium chloride at a dose of 63 mg/kg was more likely to reduce stroke volume (by 45%, P=0.004) and perifocal edema (by 35%, P=0.007). When determining lesion volume on day 7, the data were comparable to those obtained on day 2. With the 21 mg/kg dose, stroke volume was 20% lower than in the control group (P=0.04). Lithium chloride, 63 mg/kg, reduced stroke volume by 40% (P=0.004).Conclusion. Lithium chloride dose affects necrotic focus formation and manifestations of perifocal cerebral edema after middle cerebral artery occlusion. The maximum reduction in the volume of ischemic stroke and perifocal edema was observed when the 63 mg/kg dose was used.
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Borson, D. B., J. J. Brokaw, K. Sekizawa, D. M. McDonald, and J. A. Nadel. "Neutral endopeptidase and neurogenic inflammation in rats with respiratory infections." Journal of Applied Physiology 66, no. 6 (June 1, 1989): 2653–58. http://dx.doi.org/10.1152/jappl.1989.66.6.2653.
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Neuropeptides such as substance P are implicated in inflammation mediated by sensory nerves (neurogenic inflammation), but the roles in disease of these peptides and the peptidases that degrade them are not understood. It is well established that inflammation is a prominent feature of several airway diseases, including viral infections, asthma, bronchitis, and cystic fibrosis. These diseases are characterized by cough, airway edema, and abnormal secretory and bronchoconstrictor responses, all of which can be elicited by substance P. The effects of substance P and other peptides that may be involved in inflammation are decreased by endogenous neutral endopeptidase (NEP; also called enkephalinase, EC 3.4.24.11), which is a peptidase that degrades substance P and other peptides. In the present study, we report that rats with histories of infections caused by common respiratory tract pathogens (parainfluenza virus type 1, rat corona-virus, and Mycoplasma pulmonis) not only have greater susceptibility to neurogenic inflammatory responses than do pathogen-free rats but also have a lower activity of NEP in the trachea. This reduction in NEP activity may cause the increased susceptibility to neurogenic inflammation by allowing higher concentrations of substance P to reach tachykinin receptors in the trachea. Thus decreased NEP activity may exacerbate some of the pathological responses in animals with respiratory tract infections.
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Jacewicz, Michael, Steve Brint, Jody Tanabe, and William A. Pulsinelli. "Continuous Nimodipine Treatment Attenuates Cortical Infarction in Rats Subjected to 24 Hours of Focal Cerebral Ischemia." Journal of Cerebral Blood Flow & Metabolism 10, no. 1 (January 1990): 89–96. http://dx.doi.org/10.1038/jcbfm.1990.11.
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Focal cerebral infarction and edema were measured in rats (Wistar, Fisher 344, and spontaneously hypertensive strains) pretreated with nimodipine (2 μg/kg/min i.v.) or its vehicle and subjected to the tandem occlusion of the middle cerebral and common carotid arteries. Animals awoke from anesthesia 10–15 min after onset of ischemia and continued to receive treatment over a 24-h survival period. Cortical infarction and edema were quantified by image analysis of frozen brain sections processed for histology. Nimodipine-treated rats developed 20–60% smaller cortical infarct volumes than controls (p < 0.002). Cortical edema was reduced proportionately to the decrease in infarct volume and constituted ∼36% of the infarct volume. Nimodipine caused a mild hypotensive response that did not aggravate ischemic brain damage. The results indicate that continuous nimodipine treatment, started before induction of focal cerebral ischemia, can attenuate ischemic brain damage and edema as late as 24 h after the onset of ischemia.
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Mohanty, Sureswar, Srikant Kumar Swain, and Chinmay Biswal. "Brain Edema: Newer Concept of Treatment." Annals of the National Academy of Medical Sciences (India) 55, no. 04 (October 2019): 189–92. http://dx.doi.org/10.1055/s-0040-1701154.
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AbstractBrain edema is excess accumulation of water in intracellular or extracellular spaces of the brain. It may be due to traumatic brain injury, neoplasm, infection, or following surgery. Advent of electron microscope and molecular pathophysiology of fluid transport through blood–brain barrier has elucidated the mechanism of edema formation, that is, ion channels and transport of fluid into extracellular space. Currently approved treatments, such as decompressive craniectomy and osmotherapy, controlled hyperventilation, and administration of diuretics, were developed prior to any knowledge of modern cerebral edema pathophysiology. These therapies attempt to manage downstream end-stage events without directly attenuating the underlying molecular mechanisms of cerebral edema. Next few years will yield new knowledge of how particular proteins drive edema influx, paving the way for rationally designed therapeutics that directly target key steps in cerebral edema formation, thereby achieving what currently approved therapies do not. Pharmacological agents which can block edema formation are being tried experimentally and clinically. Development in imaging, that is, computed tomography and diffusion tensor magnetic resonance imaging, has helped in antemortem assessment of evolution and resolution of brain edema as a dynamic pathophysiology. Animal studies shows release of vasoactive substances, that is, histamine, serotonin, adrenaline, nitric oxide, substance P, prostaglandins, tumor necrosis factor-α, and cytokines, in the injured brain results in activation of inflammatory cascade, which is the important cause of brain edema.
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Noble, Marc D., Joelle Romac, Yu Wang, Jay Hsu, John E. Humphrey, and Rodger A. Liddle. "Local disruption of the celiac ganglion inhibits substance P release and ameliorates caerulein-induced pancreatitis in rats." American Journal of Physiology-Gastrointestinal and Liver Physiology 291, no. 1 (July 2006): G128—G134. http://dx.doi.org/10.1152/ajpgi.00442.2005.
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Primary sensory neurons of the C and Aδ subtypes express the vanilloid capsaicin receptor TRPV1 and contain proinflammatory peptides such as substance P (SP) that mediate neurogenic inflammation. Pancreatic injury stimulates these neurons causing the release of SP in the pancreas resulting in pancreatic edema and neutrophil infiltration that contributes to pancreatitis. Axons of primary sensory neurons innervating the pancreas course through the celiac ganglion. We hypothesized that disruption of the celiac ganglion by surgical excision or inhibition of C and Aδ fibers through blockade of TRPV1 would reduce the severity of experimental pancreatitis by inhibiting neurogenic inflammation. Resiniferatoxin (RTX) is a specific TRPV1 agonist that, in high doses, selectively destroys C and Aδ fibers. Sprague-Dawley rats underwent surgical ganglionectomy or application of 10 μg RTX (vs. vehicle alone) to the celiac ganglion. One week later, pancreatitis was induced by six hourly intraperitoneal injections of caerulein (50 μg/kg). The severity of pancreatitis was assessed by serum amylase, pancreatic edema, and pancreatic myeloperoxidase (MPO) activity. SP receptor (neurokinin-1 receptor, NK-1R) internalization in acinar cells, used as an index of endogenous SP release, was assessed by immunocytochemical quantification of NK-1R endocytosis. Caerulein administration caused significant increases in pancreatic edema, serum amylase, MPO activity, and NK-1R internalization. RTX treatment and ganglionectomy significantly reduced pancreatic edema by 46% ( P < 0.001) and NK-1R internalization by 80% and 51% ( P < 0.001 and P < 0.05, respectively). RTX administration also significantly reduced MPO activity by 47% ( P < 0.05). Neither treatment affected serum amylase, consistent with a direct effect of caerulein. These results demonstrate that disruption of or local application of RTX to the celiac ganglion inhibits SP release in the pancreas and reduces the severity of acute secretagogue-induced pancreatitis. It is possible that selectively disrupting TRPV1-bearing neurons could be used to reduce pancreatitis severity.
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Hosomi, Naohisa, Camelia R. Ban, Takayuki Naya, Tsutomu Takahashi, Peng Guo, Xiao-yu R. Song, and Masakazu Kohno. "Tumor Necrosis Factor-α Neutralization Reduced Cerebral Edema Through Inhibition of Matrix Metalloproteinase Production After Transient Focal Cerebral Ischemia." Journal of Cerebral Blood Flow & Metabolism 25, no. 8 (February 23, 2005): 959–67. http://dx.doi.org/10.1038/sj.jcbfm.9600086.
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After focal cerebral ischemia, tumor necrosis factor-α deteriorates cerebral edema and survival rate. Therefore, tumor necrosis factor-α neutralization could reduce cerebral microvascular permeability in acute cerebral ischemia. Left middle cerebral artery occlusion for 120 mins followed by reperfusion was performed with the thread method under halothane anesthesia in Sprague-Dawley rats. Antirat tumor necrosis factor-α neutralizing monoclonal antibody with a rat IgG Fc portion (15 mg/kg) was infused intravenously right after reperfusion. Stroke index score, infarct volume, cerebral specific gravity, and the endogenous expression of tumor necrosis factor-α, matrix metalloproteinase (MMP)-2, MMP-9, and membrane type 1-MMP in the brain tissue were quantified in the ischemic and matched contralateral nonischemic hemisphere. In the antitumor necrosis factor-α neutralizing antibody-treated rats, infarct volume was significantly reduced ( P = 0.014, n = 7; respectively), and cerebral specific gravity was dramatically increased in the cortex and caudate putamen ( P<0.001, n = 7; respectively) in association with a reduction in MMP-9 and membrane type 1-MMP upregulation. Tumor necrosis factor-α in the brain tissue was significantly elevated in the ischemic hemisphere 6 h after reperfusion in the nonspecific IgG-treated rats ( P = 0.021, n = 7) and was decreased in the antitumor necrosis factor-α neutralizing antibody-treated rats ( P = 0.001, n = 7). Postreperfusion treatment with antirat tumor necrosis factor-α neutralizing antibody reduced brain infarct volume and cerebral edema, which is likely mediated by a reduction in MMP upregulation.
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Zee, Eric D., Stacey Schomberg, and Todd C. Carpenter. "Hypoxia upregulates lung microvascular neurokinin-1 receptor expression." American Journal of Physiology-Lung Cellular and Molecular Physiology 291, no. 1 (July 2006): L102—L110. http://dx.doi.org/10.1152/ajplung.00286.2005.
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Subacute exposure to moderate hypoxia can promote pulmonary edema formation. The tachykinins, a family of proinflammatory neuropeptides, have been implicated in the pathogenesis of pulmonary edema in some settings, including the pulmonary vascular leak associated with exposure to hypoxia. The effects of hypoxia on tachykinin receptor and peptide expression in the lung, however, remain poorly understood. We hypothesized that subacute exposure to moderate hypoxia increases lung neurokinin-1 (NK-1) receptor expression as well as lung substance P levels. We tested this hypothesis by exposing weanling Sprague-Dawley rats to hypobaric hypoxia (barometric pressure 0.5 atm) for 0, 24, 48, or 72 h. Hypoxia led to time-dependent increases in lung NK-1 receptor mRNA expression and lung NK-1 receptor protein levels at 48 and 72 h of exposure ( P < 0.05). Immunohistochemistry and in situ NK-1 receptor labeling with substance P-conjugated fluorescent nanocrystals demonstrated that hypoxia increased NK-1 expression primarily in the pulmonary microvasculature and in alveolar macrophages. Hypoxia also led to increases in lung substance P levels by 48 and 72 h ( P < 0.05) but led to a decrease in preprotachykinin mRNA levels ( P < 0.05). We conclude that subacute exposure to moderate hypoxia upregulates lung NK-1 receptor expression and lung substance P peptide levels primarily in the lung microvasculature. We speculate that this effect may contribute to the formation of pulmonary edema in the setting of regional or environmental hypoxia.
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Juenemann, Martin, Tobias Braun, Nadine Schleicher, Mesut Yeniguen, Patrick Schramm, Tibo Gerriets, Nouha Ritschel, et al. "Neuroprotective mechanisms of erythropoietin in a rat stroke model." Translational Neuroscience 11, no. 1 (May 18, 2020): 48–59. http://dx.doi.org/10.1515/tnsci-2020-0008.
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AbstractObjectiveThis study was designed to investigate the indirect neuroprotective properties of recombinant human erythropoietin (rhEPO) pretreatment in a rat model of transient middle cerebral artery occlusion (MCAO).MethodsOne hundred and ten male Wistar rats were randomly assigned to four groups receiving either 5,000 IU/kg rhEPO intravenously or saline 15 minutes prior to MCAO and bilateral craniectomy or sham craniectomy. Bilateral craniectomy aimed at elimination of the space-consuming effect of postischemic edema. Diagnostic workup included neurological examination, assessment of infarct size and cerebral edema by magnetic resonance imaging, wet–dry technique, and quantification of hemispheric and local cerebral blood flow (CBF) by flat-panel volumetric computed tomography.ResultsIn the absence of craniectomy, EPO pretreatment led to a significant reduction in infarct volume (34.83 ± 9.84% vs. 25.28 ± 7.03%; p = 0.022) and midline shift (0.114 ± 0.023 cm vs. 0.083 ± 0.027 cm; p = 0.013). We observed a significant increase in regional CBF in cortical areas of the ischemic infarct (72.29 ± 24.00% vs. 105.53 ± 33.10%; p = 0.043) but not the whole hemispheres. Infarct size-independent parameters could not demonstrate a statistically significant reduction in cerebral edema with EPO treatment.ConclusionsSingle-dose pretreatment with rhEPO 5,000 IU/kg significantly reduces ischemic lesion volume and increases local CBF in penumbral areas of ischemia 24 h after transient MCAO in rats. Data suggest indirect neuroprotection from edema and the resultant pressure-reducing and blood flow-increasing effects mediated by EPO.
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Jin, Shuo-guo, Ji-li Deng, Ze-ran Chen, Fang Yang, Mei-jun Liu, Hong-hui Sun, Ning-jing Ran, Li Zhang, Dong-dong Yang, and Wei-yin Chen. "Pretreatment with Shenxiong Drop Pill induces AQP4- mediated neuroprotective effect on middle cerebral artery occlusion in rats." Tropical Journal of Pharmaceutical Research 19, no. 8 (November 20, 2020): 1715–22. http://dx.doi.org/10.4314/tjpr.v19i8.21.
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Purpose: To investigate the neuroprotective effect of Shenxiong Drop Pill (SXDP) pretreatment on rats with middle cerebral artery occlusion (MCAO) in rats, and the mechanism involved.Methods: Ninety-nine SD rats were randomly assigned to 4 groups: control group, MCAO group, shamoperated group and SXDP group. The MCAO model was established via thread occlusion. Rats in the SXDP group was administered SXDP 7 days before induction of MCAO. Neurological deficit score (NDS) was determined using Bederson's neurological behavioral scoring method, while cerebral infarction volume was measured using TTC staining. Integrated optical density (IOD) of Nissl Body was evaluated via Nissl staining. Brain water content was measured using dry-wet method. The expression level of AQP4 in brain tissues was determined using immunocytochemistry.Results: The SXDP treatment resulted in significant reduction in NDS, marked improvement in IOD of Nissl Body, and significant reductions in cerebral infarction volume, brain water content, and expression level of AQP4, relative to control (p< 0.05).Conclusion: These results suggest that SXDP pretreatment exerts neuroprotective effect against cerebral ischemia in rats by decreasing in cerebral edema through a mechanism involving downregulation of the expression of AQP4.
Keywords: Middle cerebral artery occlusion, Cerebral ischemia, Aquaporins-4, Cerebral edema, Neuroprotection
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Cole, D. J., J. C. Drummond, T. N. Osborne, and J. Matsumura. "Hypertension and hemodilution during cerebral ischemia reduce brain injury and edema." American Journal of Physiology-Heart and Circulatory Physiology 259, no. 1 (July 1, 1990): H211—H217. http://dx.doi.org/10.1152/ajpheart.1990.259.1.h211.
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The extent of cerebral injury and edema was determined in isoflurane-anesthetized rats (n = 32) after 180 min of middle cerebral artery occlusion (MCAO) and 120 min of reperfusion. One of the following was employed during the occlusion period only: 1) control, mean arterial pressure [MAP = 131 +/- 7 (SD) mmHg] and hematocrit (43 +/- 2%) were not manipulated; 2) hemodilution, the hematocrit was reduced to 30% with 5% albumin (MAP = 104 +/- 19 mmHg); 3) hemodilution-normotension, hemodilution was established, and MAP was maintained at 131 +/- 9 mmHg with phenylephrine; 4) hemodilution-hypertension, hemodilution was established, and MAP increased to 161 +/- 2 mmHg with phenylephrine. Brain injury was determined with 2,3,5-triphenyltetrazolium chloride, and cerebral edema was assessed by microgravimetry. Brain injury and cerebral edema were less in both phenylephrine groups, compared with the control and hemodilution groups (P less than 0.05). These results are consistent with the premise that if normotension is maintained, hemodilution reduces ischemic brain injury and edema. They also indicate that the addition of phenylephrine-induced hypertension to hemodilution therapy results in a further reduction of ischemic injury without exacerbating cerebral edema.
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Voronkov, A. V., D. I. Pozdnyakov, and S. A. Nigaryan. "Сerebroprotective effect of some phenolic acids under conditions of experimental brain ischemia." Pharmacy & Pharmacology 7, no. 6 (January 17, 2020): 332–39. http://dx.doi.org/10.19163/2307-9266-2019-7-6-332-338.
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The aim of the study was to evaluate the cerebroprotective effect of some phenolic acids under the conditions of experimental cerebral ischemia in rats.Materials and methods. The experiment was conducted on male Wistar rats weighing 220–240 g. Focal cerebral ischemia was modeled by irreversible right-sided thermocoagulation of the middle cerebral artery under chloral hydrate anesthesia (350 mg/kg, intraperitoneally). The experimental compounds (4-hydroxy-3.5-di-tert-butyl cinnamic acid, caffeic acid and gallic acid 100 mg/kg each compound) and a reference drug (Mexicor – 100 mg/kg) were administered intragastrically next day after the surgery and then for three daysrunning. The effect of the test-compounds on the cognitive functions of the rats was evaluated by CRPA and TEA tests. The influence of the compounds on the changes in the concentration of lactate, pyruvate, homocysteine, as well as the degree of cerebral edema formation and necrosis of the brain tissue, were studied.Results. In the study, it has been established that against the background of the focal cerebral ischemia, the administration of caffeic, 4-hydroxy-3,5-di-tert-butylcinnamic and gallic acid, contributed to the preservation of a memorable trace in rats, as well as a decrease in lactate concentration (by 40.37% (p<0.05), 151.26% (p<0.05), 48.02% (p<0.05)) and pyruvate (by 96.6,% (p<0.05), 38, 78% (p<0.05), 33.3% (p<0.05)), homocysteine (by 59.6% (p<0.05), 102.18% (p<0.05), 28.8% (p<0.05)), аnecrosis zone (by 122.79% (p<0.05), 165.11% (p<0.05), 12.38% (p<0,05)) and cerebral edema (by 10.47% (p<0.05), 11.08% (p<0.05), 9.92% (p<0.05)) relative to the NC group of rats.Conclusion. The obtained data indicate the possibility of further detailed investigation of the cerebroprotective effect of 4-hydroxy-3,5-di-tert-butylcinnamic, caffeic and gallic acids.
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Belayev, Ludmila, Raul Busto, Weizhao Zhao, James A. Clemens, and Myron D. Ginsberg. "Effect of delayed albumin hemodilution on infarction volume and brain edema after transient middle cerebral artery occlusion in rats." Journal of Neurosurgery 87, no. 4 (October 1997): 595–601. http://dx.doi.org/10.3171/jns.1997.87.4.0595.
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✓ The authors examined the effect of delayed high-concentration albumin therapy on ischemic injury in a highly reproducible model of middle cerebral artery (MCA) occlusion in rats. Male Sprague—Dawley rats weighing 270 to 320 g were anesthetized with halothane and subjected to 120 minutes of temporary MCA occlusion induced by means of a poly-l-lysine—coated intraluminal nylon suture inserted retrograde via the external carotid artery into the internal carotid artery and MCA. The agent (20% human serum albumin [HSA]) or control solution (sodium chloride 0.9%) was administered intravenously at a dosage of 1% of body weight immediately after suture removal following a 2-hour period of MCA occlusion. The animals' neurological status was evaluated during MCA occlusion (at 60 minutes) and daily for 3 days thereafter. The brains were perfusion-fixed, and infarct volumes and brain edema were determined. The HSA significantly improved the neurological score compared with saline at 24 hours after MCA occlusion. The rats treated with HSA also had significantly reduced total infarct volume (by 34%) and brain edema (by 81%) compared with saline-treated rats. There was a strong correlation between hematocrit level and brain edema (p < 0.01), and between total infarct volume or brain edema and neurological score at 24, 48, and 72 hours postinjury (p < 0.0002). These results strongly support the beneficial effect of delayed albumin therapy in transient focal ischemia and indicate its possible usefulness in treating patients with acute ischemic stroke.
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Hu, Renlin, Yaming Hao, Fan Tao, Feng Wang, Weichen Zhang, and Yuxuan Tao. "Transplantation of Bone Marrow Mesenchymal Stem Cells (BMSCs) Improves Nerve Cell Function in Rats with Cerebral Infarction and Injury." Journal of Biomaterials and Tissue Engineering 12, no. 11 (November 1, 2022): 2254–59. http://dx.doi.org/10.1166/jbt.2022.3182.
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Our study intends to assess the effect of transplantation of bone marrow mesenchymal stem cells (BMSCs) on nerve cell in rats with cerebral infarction and injury. 36 healthy rats were separated into JS group (sham-operation), NG group (cerebral infarction) and YZ group (BMSCs transplantation). The arrangement of brain tissue in JS group was integrated without edema and confused in NG group with obvious edema. However, the necrosis degree of brain tissue in YZ group was alleviated. There were symptoms of muscle loss in the right foreleg and hind leg of rats in NG group. The NSS score in NG group was higher than JS group (P < 0.05), suggesting that the neurological function after BMSCs transplantation was improved. The distribution of cortical tissue was tight and nervous tissue distribution in NG group was evacuated comparatively. The quantity of nerve cell was reduced with tumescence. In conclusion, transplantation of BMSCs exerts a promising therapeutic effect on the treatment of cerebral infarction as it can improve nerve cell function, reduce oxidative stress and inflammatory cytokines secretion, and ameliorate cerebral injury.
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Lewis, Kate Marie, Renée Jade Turner, and Robert Vink. "Blocking Neurogenic Inflammation for the Treatment of Acute Disorders of the Central Nervous System." International Journal of Inflammation 2013 (2013): 1–16. http://dx.doi.org/10.1155/2013/578480.
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Classical inflammation is a well-characterized secondary response to many acute disorders of the central nervous system. However, in recent years, the role of neurogenic inflammation in the pathogenesis of neurological diseases has gained increasing attention, with a particular focus on its effects on modulation of the blood-brain barrier BBB. The neuropeptide substance P has been shown to increase blood-brain barrier permeability following acute injury to the brain and is associated with marked cerebral edema. Its release has also been shown to modulate classical inflammation. Accordingly, blocking substance P NK1 receptors may provide a novel alternative treatment to ameliorate the deleterious effects of neurogenic inflammation in the central nervous system. The purpose of this paper is to provide an overview of the role of substance P and neurogenic inflammation in acute injury to the central nervous system following traumatic brain injury, spinal cord injury, stroke, and meningitis.
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Cheney, Jessica A., Justin D. Weisser, Florence M. Bareyre, Helmut L. Laurer, Kathryn E. Saatman, Ramesh Raghupathi, Valentin Gribkoff, John E. Starrett, and Tracy K. McIntosh. "The Maxi-K Channel Opener BMS-204352 Attenuates Regional Cerebral Edema and Neurologic Motor Impairment after Experimental Brain Injury." Journal of Cerebral Blood Flow & Metabolism 21, no. 4 (April 2001): 396–403. http://dx.doi.org/10.1097/00004647-200104000-00008.
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Large-conductance, calcium-activated potassium (maxi-K) channels regulate neurotransmitter release and neuronal excitability, and openers of these channels have been shown to be neuroprotective in models of cerebral ischemia. The authors evaluated the effects of postinjury systemic administration of the maxi-K channel opener, BMS-204352, on behavioral and histologic outcome after lateral fluid percussion (FP) traumatic brain injury (TBI) in the rat. Anesthetized Sprague-Dawley rats (n = 142) were subjected to moderate FP brain injury (n = 88) or surgery without injury (n = 54) and were randomized to receive a bolus of 0.1 mg/kg BMS-204352 (n = 26, injured; n = 18, sham), 0.03 mg/kg BMS-204352 (n = 25, injured; n = 18, sham), or 2% dimethyl sulfoxide (DMSO) in polyethylene glycol (vehicle, n = 27, injured; n = 18, sham) at 10 minutes postinjury. One group of rats was tested for memory retention (Morris water maze) at 42 hours postinjury, then killed for evaluation of regional cerebral edema. A second group of injured/sham rats was assessed for neurologic motor function from 48 hours to 2 weeks postinjury and cortical lesion area. Administration of 0.1 mg/kg BMS-204352 improved neurologic motor function at 1 and 2 weeks postinjury ( P < 0.05) and reduced the extent of cerebral edema in the ipsilateral hippocampus, thalamus, and adjacent cortex ( P < 0.05). Administration of 0.03 mg/kg BMS-204352 significantly reduced cerebral edema in the ipsilateral thalamus ( P < 0.05). No effects on cognitive function or cortical tissue loss were observed with either dose. These results suggest that the novel maxi-K channel opener BMS-204352 may be selectively beneficial in the treatment of experimental TBI.
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Huang, Guo, Yamei Li, Qian Yu, Rongjian Feng, and Guanlan Zhao. "Probucol reduces the cerebral edema area and infarction volume in rat cerebral infarction model via PI3K/Akt pathway." Tropical Journal of Pharmaceutical Research 21, no. 3 (May 29, 2022): 571–77. http://dx.doi.org/10.4314/tjpr.v21i3.17.
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Purpose: To study the effects of probucol on rats with cerebral infarction through the phosphatidylinositol 3-hydroxy kinase (PI3K)/protein kinase B (Akt) pathway.Methods: Sprague-Dawley (SD) rats were divided into sham group (SO group, n = 7), model group (MO group, n = 7) and probucol group (PR group, n = 7). Infarction volume, messenger ribonucleic acid (mRNA), protein expressions of PI3K/Akt, neurological score, brain water content, degree of brain tissue lesions and neurological function score were determined.Results: Neurological score was 0, 2.54 ± 0.67 and 1.34 ± 0.21 points, in SO, O and PR groups, respectively. In turning angle test, neurological function score gradually rose at 24 h after cerebral infarction in PR and MO groups, compared with that in the SO group (p < 0.05), but significantly declined at 48 h in PR group compared with that in MO group (p < 0.05). Brain water content was lowest in the SO group but highest in MO group; it was significantly lower in PR group than that in MO group (p < 0.05). The mRNA and protein expressions of PI3K/Akt were highest in SO group and lowest in MO group; the expressions were higher in PR group than those in the MO group (p < 0.05).Conclusion: Probucol reduces the cerebral edema area and infarction volume by activating PI3K/Akt pathway, thereby exerting a significant therapeutic effect on rat model with cerebral infarction. Thus, this agent has the potential for use in the management of cerebral infarction.
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Baluk, P., and D. M. McDonald. "The beta 2-adrenergic receptor agonist formoterol reduces microvascular leakage by inhibiting endothelial gap formation." American Journal of Physiology-Lung Cellular and Molecular Physiology 266, no. 4 (April 1, 1994): L461—L468. http://dx.doi.org/10.1152/ajplung.1994.266.4.l461.
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beta 2-Adrenergic receptor agonists inhibit the increase in vascular permeability produced by a variety of inflammatory mediators. The anti-edema effect of beta 2-agonists is assumed to result from a direct action on endothelial cells, but such a mechanism has not been demonstrated in vivo. The aim of this study was to determine whether beta 2-agonists exert their anti-edema effect by inhibiting the formation of endothelial gaps at sites of plasma leakage. Vascular permeability in the rat trachea was increased by electrical stimulation of the vagus nerve or by intravenous injection of substance P (5 micrograms/kg iv). Plasma leakage was quantified by using Monastral blue and Evans blue as tracers. Endothelial gaps were made visible for light microscopy by staining the borders of endothelial cells with silver nitrate. The experiments showed that the selective beta 2-agonist formoterol, which is known to have anti-edema effects, reduced the plasma leakage produced by either stimulus. The effect was dose dependent, with a formoterol dose of 10 micrograms/kg iv producing maximal reduction of Monastral blue leakage (64 +/- 14%). The amounts of extravasation of Monastral blue and Evans blue were closely correlated (r2 = 0.76, P < 0.01). After the injection of substance P, there were 15.3 +/- 1.0 gaps/endothelial cells in postcapillary venules of vehicle-pretreated rats, but only 5.0 +/- 0.2 gaps/cell in formoterol-pretreated (10 micrograms/kg iv) rats.(ABSTRACT TRUNCATED AT 250 WORDS)
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Turner, Renee J., Peter C. Blumbergs, and Robert Vink. "A substance P antagonist improves outcome following reversible middle cerebral artery occlusion in rats." Journal of Cerebral Blood Flow & Metabolism 25, no. 1_suppl (August 2005): S32. http://dx.doi.org/10.1038/sj.jcbfm.9591524.0032.
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Ninomia, Takashi, Liang Wang, S. Ram Kumar, Anthony Kim, and Berislav V. Zlokovic. "Brain Injury and Cerebrovascular Fibrin Deposition Correlate with Reduced Antithrombotic Brain Capillary Functions in a Hypertensive Stroke Model." Journal of Cerebral Blood Flow & Metabolism 20, no. 6 (June 2000): 998–1009. http://dx.doi.org/10.1097/00004647-200006000-00012.
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Hemostasis factors may influence the pathophysiology of stroke. The role of brain hemostasis in ischemic hypertensive brain injury is not known. We studied ischemic injury in spontaneously hypertensive rats in relation to cerebrovascular fibrin deposition and activity of different hemostasis factors in brain microcirculation. In spontaneously hypertensive rats subjected to transient middle cerebral artery occlusion versus normotensive Wistar-Kyoto (W-K) rats, infarct and edema volumes were increased by 6.1-fold ( P < 0.001) and 5.8-fold ( P < 0.001), respectively, the cerebral blood flow (CBF) reduced during middle cerebral artery occlusion (MCAO) by 55% ( P < 0.01), motor neurologic score increased by 6.9-fold ( P < 0.01), and cerebrovascular fibrin deposition increased by 6.8-fold ( P < 0.01). Under basal conditions, brain capillary protein C activation and tissue plasminogen activator activity were reduced in spontaneously hypertensive rats compared with Wistar-Kyoto rats by 11.8-fold ( P < 0.001) and 5.1-fold ( P < 0.001), respectively, and the plasminogen activator inhibitor-1 antigen and tissue factor activity were increased by 154-fold ( P < 0.00001) and 74% ( P < 0.01), respectively. We suggest that hypertension reduces antithrombotic mechanisms in brain microcirculation, which may enhance cerebrovascular fibrin deposition and microvascular obstructions during transient focal cerebral ischemia, which results in greater neuronal injury.
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Jacewicz, Michael, Steve Brint, Jody Tanabe, Xing-Je Wang, and William A. Pulsinelli. "Nimodipine Pretreatment Improves Cerebral Blood Flow and Reduces Brain Edema in Conscious Rats Subjected to Focal Cerebral Ischemia." Journal of Cerebral Blood Flow & Metabolism 10, no. 6 (November 1990): 903–13. http://dx.doi.org/10.1038/jcbfm.1990.147.
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The effect of nimodipine pretreatment on CBF and brain edema was studied in conscious rats subjected to 2.5 h of focal cortical ischemia. An infusion of nimodipine (2 μg/kg/min i.v.) or its vehicle, polyethylene glycol 400, was begun 2 h before the ischemic interval and was continued throughout the survival period. Under brief halothane anesthesia, the animals' right middle cerebral and common carotid arteries were permanently occluded, and 2.5 h later, they underwent a quantitative CBF study ([14C]iodoantipyrine autoradiography followed by Quantimet 970 image analysis). Nimodipine treatment improved blood flow to the middle cerebral artery territory without evidence of a “vascular steal” and reduced the volume of the ischemic core (cortex with CBF of < 25 ml/100 g/min) and accompanying edema by ∼50% when compared with controls (p = 0.006 and 0.0004, respectively). Mild hypotension induced by nimodipine did not aggravate the ischemic insult. The ischemic core volumes, however, were 50–75% smaller than the 24-h infarct volumes generated in a similar paradigm that demonstrated 20–30% infarct reduction with continuous nimodipine treatment. These results suggest that nimodipine pretreatment attenuates the severity of early focal cerebral ischemia, but that with persistent ischemia, cortex surrounding the ischemic core undergoes progressive infarction and the early benefit of nimodipine treatment is only partly preserved.
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Pfefferkorn, T., B. Staufer, M. Liebetrau, G. Bültemeier, M. R. Vosko, C. Zimmermann, and G. F. Hamann. "Plasminogen Activation in Focal Cerebral Ischemia and Reperfusion." Journal of Cerebral Blood Flow & Metabolism 20, no. 2 (February 2000): 337–42. http://dx.doi.org/10.1097/00004647-200002000-00015.
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In focal cerebral ischemia the plasminogen-plasmin system plays a role in the fibrinolysis of vessel-occluding clots and also in the proteolysis of extracellular matrix components, which potentially contributes to brain edema and bleeding complications. The authors investigated the plasminogen activation after middle cerebral artery occlusion with and without reperfusion (reperfusion intervals 9 and 24 hours) in rats by histologic zymography and compared areas of increased plasminogen activation to areas of structural injury, which were detected immunohistochemically. After 3 hours of ischemia, increased plasminogen activation was observed in the ischemic hemisphere. The affected area measured 5.2% ± 8.5% and 19.4% ± 30.1% of the total basal ganglia and cortex area, respectively. Reperfusion for 9 hours after 3 hours of ischemia led to a significant expansion of plasminogen activation in the basal ganglia (68.8% ± 42.2%, P < 0.05) but not in the cortex (43.0% ± 34.6%, P = 0.394). In the basal ganglia, areas of increased plasminogen activation were related to areas of structural injury ( r = 0.873, P < 0.001). No such correlation was found in the cortex ( r = 0.299, P = 0.228). In this study, increased plasminogen activation was demonstrated early in focal cerebral ischemia. This activation may promote early secondary edema formation and also secondary hemorrhage after ischemic stroke.
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Frerichs, Kai U., Perttu J. Lindsberg, John M. Hallenbeck, and Giora Z. Feuerstein. "Platelet-activating factor and progressive brain damage following focal brain injury." Journal of Neurosurgery 73, no. 2 (August 1990): 223–33. http://dx.doi.org/10.3171/jns.1990.73.2.0223.
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✓ The effects of a platelet-activating factor (PAF) antagonist on brain edema, cortical microcirculation, blood-brain barrier (BBB) disruption, and neuronal death following focal brain injury are reported. A neodymium:yttrium-aluminum-garnet (Nd:YAG) laser was used to induce highly reproducible focal cortical lesions in anesthetized rats. Secondary brain damage in this model was characterized by progressive cortical hypoperfusion, edema, and BBB disruption in the vicinity of the hemispheroid lesion occurring acutely after injury. The histopathological evolution was followed for up to 4 days. Neuronal damage in the cortex and the hippocampus (CA-1) was assessed quantitatively, revealing secondary and progressive loss of neuronal tissue within the first 24 hours following injury. Pretreatment with the PAF antagonist BN 50739 ameliorated the severe hypoperfusion in 12 rats (increasing local cerebral blood flow from a mean ± standard error of the mean of 40.5% ± 8.3% to 80.2% ± 7.8%, p < 0.01) and reduced edema by 70% in 10 rats (p < 0.05) acutely after injury. The PAF antagonist also reduced the progression of neuronal damage in the cortex and the CA-1 hippocampal neurons (decrease of neuronal death from 88.0% ± 3.9% to 49.8% ± 4.2% at 24 hours in the cortex and from 40.2 ± 5.0% to 13.2% ± 2.1% in the hippocampus in 30 rats; p < 0.05). This study provides evidence to support progressive brain damage following focal brain injury, associated with secondary loss of neuronal cells. In this latter process, PAF antagonists may provide significant therapeutic protection in arresting secondary brain damage following cerebral ischemia and neurological trauma.
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Wu, Xu-Dong, Chen Wang, Zhen-Ying Zhang, Yan Fu, Feng-Ying Liu, and Xiu-Hua Liu. "PuerarinAttenuates Cerebral Damage by Improving Cerebral Microcirculation in Spontaneously Hypertensive Rats." Evidence-Based Complementary and Alternative Medicine 2014 (2014): 1–7. http://dx.doi.org/10.1155/2014/408501.
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Puerariae Lobatae Radix(Gegen in Chinese) is the dried root ofPueraria lobata, a semiwoody, perennial, and leguminous vine native to China.Puerarinis one of the effective components of isoflavones isolated from the root ofPueraria lobata. Previous studies showed that extracts derived from the root ofPueraria lobatapossessed antihypertensive effect. Our study is to investigate whetherpuerarincontributes to prevention of stroke by improving cerebral microcirculation in rats.Materials and Methods. Video microscopy and laser Doppler perfusion imaging on the pia mater were used to measure the diameter of microvessel and blood perfusion in 12-week old spontaneously hypertensive rats (SHRs) and age-matched normotensive WKY rats. Histological alterations were observed by hematoxylin and eosin staining, and microvessel density in cerebral tissue was measured by immunohistochemical analysis with anti-Factor VIII antibody. Cell proliferation was detected by [3H]-TdR incorporation, and activities of p42/44 mitogen activated protein kinases (p42/44 MAPKs) were detected by western blot analysis in cultured cerebral microvascular endothelial cells (MECs).Results. Intravenous injection ofpuerarinrelaxed arterioles and increased the blood flow perfusion in the pia mater in SHRs.Puerarintreatment for 14 days reduced the blood pressure to a normal level in SHRs (P<0.05) and increased the arteriole diameter in the pia mater significantly as compared with vehicle treatment. Arteriole remodeling, edema, and ischemia in cerebral tissue were attenuated inpuerarin-treated SHRs. Microvessel density in cerebral tissue was greater withpuerarinthan with vehicle treatment.Puerarin-treated MECs showed greater proliferation and p42/44 MAPKs activities than vehicle treatment.Conclusions.Puerarinpossesses effects of antihypertension and stroke prevention by improved microcirculation in SHRs, which results from the increase in cerebral blood perfusion both by arteriole relaxation and p42/44 MAPKs-mediated angiogenesis.
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Ratilal, Bernardo Oliveira, Mariana Moreira Coutinho Arroja, Joao Pedro Fidalgo Rocha, Adelaide Maria Afonso Fernandes, Andreia Pereira Barateiro, Dora Maria Tuna Oliveira Brites, Rui Manuel Amaro Pinto, Bruno Miguel Nogueira Sepodes, and Helder Dias Mota-Filipe. "Neuroprotective effects of erythropoietin pretreatment in a rodent model of transient middle cerebral artery occlusion." Journal of Neurosurgery 121, no. 1 (July 2014): 55–62. http://dx.doi.org/10.3171/2014.2.jns132197.
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Object There is an unmet clinical need to develop neuroprotective agents for neurosurgical and endovascular procedures that require transient cerebral artery occlusion. The aim in this study was to explore the effects of a single dose of recombinant human erythropoietin (rhEPO) before middle cerebral artery (MCA) occlusion in a focal cerebral ischemia/reperfusion model. Methods Twenty-eight adult male Wistar rats were subjected to right MCA occlusion via the intraluminal thread technique for 60 minutes under continuous cortical perfusion monitoring by laser Doppler flowmetry. Rats were divided into 2 groups: control and treatment. In the treated group, rhEPO (1000 IU/kg intravenously) was administered 10 minutes before the onset of the MCA ischemia. At 24-hour reperfusion, animals were examined for neurological deficits, blood samples were collected, and animals were killed. The following parameters were evaluated: brain infarct volume, ipsilateral hemispheric edema, neuron-specific enolase plasma levels, parenchyma histological features (H & E staining), Fluoro-Jade–positive neurons, p-Akt and total Akt expression by Western blot analysis, and p-Akt–positive nuclei by immunohistochemical investigation. Results Infarct volume and Fluoro-Jade staining of degenerating neurons in the infarct area did not vary between groups. The severity of neurological deficit (p < 0.001), amount of brain edema (78% reduction in treatment group, p < 0.001), and neuron-specific enolase plasma levels (p < 0.001) were reduced in the treatment group. Perivascular edema was histologically less marked in the treatment group. No variations in the expression or localization of p-Akt were seen. Conclusions Administration of rhEPO before the onset of 60-minute transient MCA ischemia protected the brain from this insult. It is unlikely that rhEPO pretreatment leads to direct neuronal antiapoptotic effects, as supported by the lack of Akt activation, and its benefits are most probably related to an indirect effect on brain edema as a consequence of blood-brain barrier preservation. Although research on EPO derivatives is increasing, rhEPO acts through distinct neuroprotective pathways and its clinical safety profile is well known. Clinically available rhEPO is a potential therapy for prevention of neuronal injury induced by transitory artery occlusion during neurovascular procedures.
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Hong, K. W., K. M. Pyo, W. S. Lee, S. S. Yu, and B. Y. Rhim. "Pharmacological evidence that calcitonin gene-related peptide is implicated in cerebral autoregulation." American Journal of Physiology-Heart and Circulatory Physiology 266, no. 1 (January 1, 1994): H11—H16. http://dx.doi.org/10.1152/ajpheart.1994.266.1.h11.
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In anesthetized rats, we examined the possibility that calcitonin gene-related peptide (CGRP, a neuropeptide) released in response to transient hypotension may contribute to the reflex autoregulation of cerebral blood flow. Changes in pial arterial diameter (mean 33.0 +/- 1.1 microns) with changes in systemic arterial blood pressure (mean 101.9 +/- 2.7 mmHg) were observed directly through a closed cranial window. In capsaicin-treated rats (depletor of CGRP and substance P, 50 nmol capsaicin injected intracisternally 24 h before experiment), vasodilatation, which was evoked on transient hypotension, and vasoconstriction on reverse of hypotension were markedly attenuated or almost abolished. When changes in pial arterial diameter were plotted as a function of changes in blood pressure, the slopes of regression lines for vasodilatation and vasoconstriction were markedly reduced after capsaicin treatment. Similar reductions were evidenced under suffusion of CGRP antibody serum (1:1,000) and after CGRP receptor desensitization but not after substance P receptor desensitization. Pretreatment with glibenclamide, a K(+)-channel antagonist, also caused severe alterations in the autoregulatory vasomotor responses to hypotension and its reverse. Suffusion with mock cerebrospinal fluid, containing either CGRP or cromakalim, a K(+)-channel opener, dilated the pial artery in a concentration-dependent manner, and their effects were antagonized by glibenclamide. Substance P produced a vasodilatation, which was unaffected by glibenclamide.(ABSTRACT TRUNCATED AT 250 WORDS)
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Mintorovitch, Jan, G. Y. Yang, Hiroaki Shimizu, John Kucharczyk, Pak H. Chan, and Philip R. Weinstein. "Diffusion-Weighted Magnetic Resonance Imaging of Acute Focal Cerebral Ischemia: Comparison of Signal Intensity with Changes in Brain Water and Na+,K+ -ATPase Activity." Journal of Cerebral Blood Flow & Metabolism 14, no. 2 (March 1994): 332–36. http://dx.doi.org/10.1038/jcbfm.1994.40.
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Diffusion-weighted magnetic resonance (MR) images from rats during acute cerebral ischemia induced by middle cerebral artery occlusion were analyzed for correspondence with changes in brain water, cation concentrations, and Na+,K+-ATPase activity measured in vitro after 30 or 60 min of ischemia. In the ischemic hemisphere, signal intensity was increased at 30 min (p < 0.05 vs contralateral hemisphere) and further increased at 60 min. Na+,K+-ATPase activity was 34% lower in ischemic cortex and 40% lower in ischemic basal ganglia after 30 min (p < 0.05), but water content and Na+ and K+ concentrations were not significantly different between hemispheres. After 60 min, water content and Na+ concentration were increased, and both Na+,K+-ATPase activity and K+ concentration were decreased in the ischemic hemisphere (p < 0.05). These findings are consistent with the hypothesis that the early onset of signal hyperintensity in diffusion-weighted MR images may reflect cellular edema associated with impaired membrane pump function. Early in vivo detection and localization of potentially reversible ischemic cerebral edema may have important research and clinical applications.
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Rosenberg, Gary A., Milo Navratil, Frank Barone, and Giora Feuerstein. "Proteolytic Cascade Enzymes Increase in Focal Cerebral Ischemia in Rat." Journal of Cerebral Blood Flow & Metabolism 16, no. 3 (May 1996): 360–66. http://dx.doi.org/10.1097/00004647-199605000-00002.
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Cerebral infarction initiates a cascade of molecular events, leading to proteolytic cell death. Matrix-degrading metalloproteinases (MMPs) are neutral proteases involved in extracellular matrix damage. Type IV collagenase is an MMP that increases cerebral capillary permeability after intracerebral injection and may be important along with plasminogen activators (PA) in secondary brain edema in stroke. Therefore, we measured MMPs and PAs in spontaneously hypertensive (SHR) or Wistar-Kyoto (WKY) rats with permanent middle cerebral artery occlusion (MCAO). Brain tissue was assayed for MMPs and PAs at 1, 3, 12, and 24 h and 5 days after occlusion, using substrate gel Polyacrylamide electrophoresis (zymography). SHR showed an increase in 92-kDa type IV collagenase (gelatinase B) in the infarcted hemisphere compared with the opposite side at 12 and 24 h ( p < 0.05). Gelatinase A remained the same in both infarcted and normal tissue until 5 days after injury, when it increased significantly ( p < 0.05). Urokinase-type PA was increased significantly at 12 and 24 h and 5 days, while tissue-type PA was decreased significantly at 1, 12, and 24 h in the ischemic compared with the nonischemic hemisphere. Gelatinase B was markedly increased in SHR at 12 and 24 h compared with WKY ( p < 0.05). Secondary vasogenic edema is maximal 1–2 days after a stroke, which is the time that gelatinase B was elevated. The time of appearance of gelatinase B suggests a role in secondary tissue damage and vasogenic edema, while gelatinase A may be involved in tissue repair.
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Baechli, Heidi, Melika Behzad, Matthias Schreckenberger, Hans-Georg Buchholz, Axel Heimann, Oliver Kempski, and Beat Alessandri. "Blood Constituents Trigger Brain Swelling, Tissue Death, and Reduction of Glucose Metabolism Early after Acute Subdural Hematoma in Rats." Journal of Cerebral Blood Flow & Metabolism 30, no. 3 (November 4, 2009): 576–85. http://dx.doi.org/10.1038/jcbfm.2009.230.
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Outcome from acute subdural hematoma is often worse than would be expected from the pure increase of intracranial volume by bleeding. The aim was to test whether volume-independent pathomechanisms aggravate damage by comparing the effects of blood infusion with those of an inert fluid, paraffin oil, on intracranial pressure (ICP), cerebral perfusion pressure (CPP), local cerebral blood flow (CBF), edema formation, glucose metabolism ([18F]-deoxyglucose, MicroPET), and histological outcome. Rats were injured by subdural infusion of 300 μL venous blood or paraffin. ICP, CPP, and CBF changes, assessed during the first 30 mins after injury, were not different between the injury groups at most time points ( n=8 per group). Already at 2 h after injury, blood caused a significantly more pronounced decrease in glucose metabolism in the injured cortex when compared with paraffin ( P<0.001, n=5 per group). Ipsilateral brain edema did not differ between groups at 2 h, but was significantly more pronounced in the blood-treated groups at 24 and 48 h after injury ( n=8 per group). These changes caused a 56.2% larger lesion after blood when compared with paraffin (48.1±23.0 versus 21.1±11.8 mm3; P<0.02). Blood constituent-triggered pathomechanisms aggravate the immediate effects due to ICP, CPP, and CBF during hemorrhage and lead to early reduction of glucose metabolism followed by more severe edema and histological damage.
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Thal, Serge C., Sonja Sporer, Mariusz Klopotowski, Simone E. Thal, Johannes Woitzik, Robert Schmid-Elsaesser, Nikolaus Plesnila, and Stefan Zausinger. "Brain edema formation and neurological impairment after subarachnoid hemorrhage in rats." Journal of Neurosurgery 111, no. 5 (November 2009): 988–94. http://dx.doi.org/10.3171/2009.3.jns08412.
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Object Global cerebral edema is an independent risk factor for early death and poor outcome after subarachnoid hemorrhage (SAH). In the present study, the time course of brain edema formation, neurological deficits, and neuronal cell loss were investigated in the rat filament SAH model. Methods Brain water content and neurological deficits were determined in rats randomized to sham (1-, 24-, or 48-hour survival), SAH by endovascular perforation (1-, 24-, or 48-hour survival), or no surgery (control). The neuronal cell count (CA1–3) was quantified in a separate set of SAH (6-, 24-, 48-, or 72-hour survival) and shamoperated animals. Results Brain water content increased significantly 24 (80.2 ± 0.4% [SAH] vs 79.2 ± 0.1% [sham]) and 48 hours (79.8 ± 0.2% [SAH] vs 79.3 ± 0.1% [sham]) after SAH. The neuroscore was significantly worse after SAH (33 ± 15 [24 hours after SAH] vs 0 ± 0 points [sham]) and correlated with the extent of brain edema formation (r = 0.96, p < 0.001). No hippocampal damage was present up to 72 hours after SAH. Conclusions Brain water content and neurological dysfunction reached a maximum at 24 hours after SAH. This time point, therefore, seems to be optimal to test the effects of therapeutic interventions on brain edema formation. Neuronal cell loss was not present in CA1–3 up to 72 hours of SAH. Therefore, morphological damage needs to be evaluated at later time points.
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Gerriets, Tibo, Maureen Walberer, Nouha Ritschel, Marlene Tschernatsch, Clemens Mueller, Georg Bachmann, Markus Schoenburg, Manfred Kaps, and Max Nedelmann. "Edema formation in the hyperacute phase of ischemic stroke." Journal of Neurosurgery 111, no. 5 (November 2009): 1036–42. http://dx.doi.org/10.3171/2009.3.jns081040.
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Object Brain edema formation is a serious complication of ischemic stroke and can lead to mechanical compression of adjacent brain structures, cerebral herniation, and death. Furthermore, the space-occupying effect of edema impairs regional cerebral blood flow (rCBF), which is particularly important in the penumbra phase of stroke. In the present study, the authors evaluated the natural course of edema formation in the hyperacute phase of focal cerebral ischemia. Methods Middle cerebral artery occlusion (MCAO) or a sham procedure was performed in rats within an MR imaging unit (in-bore occlusion). Both pre- and postischemic images could be compared on a pixel-by-pixel basis. The T2 relaxation time (T2RT), a marker for brain water content, was measured in regions of interest. Results A significant increase in the T2RT was detectable as early as 20–45 minutes after MCAO. At this early time point the midline shift (MLS) amounted to 0.214 ± 0.092 cm in the MCAO group and 0.061 ± 0.063 cm in the sham group (p < 0.007). The T2RT and MLS increased linearly thereafter. Evans blue dye was intravenously injected in additional animals 20 and 155 minutes after MCAO. Extravasation of the dye was visible in all animals, indicating increased permeability of the blood-brain barrier. Conclusions Vasogenic brain edema occurs much earlier than expected following permanent MCAO and leads to MLS and mechanical compression of adjacent brain structures. Since compression effects can impair rCBF, early edema formation can significantly contribute to infarct formation and thus represents a promising target for neuroprotection.
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Ito, Junki, Anthony Marmarou, Pál Barzó, Panos Fatouros, and Frank Corwin. "Characterization of edema by diffusion-weighted imaging in experimental traumatic brain injury." Journal of Neurosurgery 84, no. 1 (January 1996): 97–103. http://dx.doi.org/10.3171/jns.1996.84.1.0097.
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✓ The objective of this study was to use diffusion-weighted magnetic resonance imaging (DWI) to help detect the type of edema that develops after experimental trauma and trauma coupled with hypotension and hypoxia (THH). Reduction in the apparent diffusion coefficients (ADCs) is thought to represent cytotoxic edema. In a preliminary series of experiments, the infusion edema model and middle cerebral artery occlusion models were used to confirm the direction of ADC change in response to purely extracellular and cytotoxic edema, respectively. The ADCs increased (p < 0.05) in the case of extracellular edema and decreased (p < 0.001) in cytotoxic edema. Following these initial experiments, a new impact acceleration model was used to induce traumatic brain injury. Thirty-six adult Sprague-Dawley rats were separated into four groups: sham, trauma alone, hypoxia and hypotension (HH), and THH. Following trauma, a 30-minute insult of hypoxia (PaO2 of 40 mm Hg) and hypotension (mean arterial blood pressure (MABP) of 30 mm Hg) were imposed and the animals were resuscitated. The DWI was carried out at four 1-hour intervals postinjury, and MABP, intracranial pressure (ICP), cerebral perfusion pressure (CPP), and cerebral blood flow (CBF) were monitored. The ADCs in the control and HH groups remained unchanged. The ADCs in the THH group rapidly decreased from a control level of 0.68 ± 0.05 × 10−3 mm2/second to 0.37 ± 0.09 3 10−3 mm2/second by 3 hours posttrauma (p < 0.001). In this group, the decreased CBF and CPP during secondary insult remained low despite resuscitation, with the ICP increasing to 56 6 7 mm Hg by 3 hours. In the trauma alone group, the rise in ICP reached a maximum value (28 ± 3 mm Hg) at 30 minutes with a significant and sustained increase in CBF despite a gradual decrease in CPP. The ADCs in this group were not significantly reduced. The data lead the authors to suggest that the rise in ICP following severe trauma coupled with secondary insult in this model is predominately caused by cytotoxic edema and that ischemia plays a major role in the development of brain edema after head injury.
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Unger, Banappa S., and Himasaila M. "PHARMACOLOGICAL EVALUATION OF PIRACETAM AND VANADYL SULFATE ON EXPERIMENTALLY INDUCED CEREBRAL ISCHEMIA IN RATS." International Journal of Pharmacy and Pharmaceutical Sciences 8, no. 9 (September 1, 2016): 178. http://dx.doi.org/10.22159/ijpps.2016v8i9.12875.
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<p><strong>Objective: </strong>The aim of present study was designed to evaluate the combinatorial effect of piracetam and vanadyl sulfate on experimentally induced global cerebral ischemia in rats.</p><p><strong>Methods: </strong>Piracetam (600 mg/kg, p. o.) and vanadyl sulfate (22.4 mg/kg, p. o.) were administered individually and also in combination before the induction of ischemia. Cerebral ischemia was induced by bilateral carotid artery (BCA) occlusion for 30 min followed by reperfusion 60 min.</p><p><strong>Results: </strong>The antioxidant and non-antioxidant enzymatic levels were estimated along with histopathological studies. The concomitant pretreated group showed a more significant decrease in lipid peroxidation (LPO) and increased in the superoxide dismutase (SOD), catalase (CAT), glutathione (GSH) and total thiol levels as compared to ischemic reperfusion group. Histopathological damage was significantly reduced in drug treated groups as compared to ischemia-reperfusion group.</p><p><strong>Conclusion: </strong>The findings of the present study suggest that pretreatment with piracetam and vanadyl sulfate in combination prevents the ischemia-reperfusion injury and prevented oxidative tissue damage as shown by decreased lipid peroxides, restored the antioxidant levels, histological changes such as infarct area, inflammatory changes, and edema.</p>
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Liu, Xin-Feng, John R. Fawcett, Robert G. Thorne, and William H. Frey. "Intranasal IGF-1 Protects against Transient Focal Cerebral Ischemia in Rats following Middle Cerebral Artery Occlusion (MCAO)." Stroke 32, suppl_1 (January 2001): 352. http://dx.doi.org/10.1161/str.32.suppl_1.352.
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P71 Insulin-like growth factor-1 (IGF-1) has been shown to protect against stroke in rats when administered intracerebroventricularly. However, this administration method is not practical in humans as it requires surgery with the risk of infection. Intranasal (IN) delivery is a noninvasive method of bypassing the blood-brain barrier to deliver IGF-1 to the brain [Thorne et al. (1999) Growth Hormone and IGF Research 9: 387]. We have assessed the therapeutic potential of IN IGF-1 in rats following experimentally-induced focal cerebral ischemia and reperfusion. Rats were given a total of three 75 μg doses of IGF-1 (Chiron Corp.) IN over the course of the 72 hour study: 10 minutes after the onset of two hours of MCAO and then again 24 and 48 hours later. Five neurologic tests assessing motor, sensory, vestibulomotor and somatosensory functions were performed at 4, 24, 48 and 72 hours after the onset of MCAO under blinded conditions. Infarct volume, hemispheric swelling and pathological changes were evaluated at 72 hours after MCAO following euthanasia and coding for blind analysis. IGF-1 treatment significantly reduced the corrected infarct volume by 71 % (p=0.002) and hemispheric swelling by 37 % (p=0.017) when compared to vehicle-treated controls. In addition, the postural reflex and flexor response tests showed significant neurologic improvement with IGF-1 treatment (p=0.016 and 0.019 respectively). The adhesive-backed paper test showed borderline significance in both the contact and removal times (p=0.0573 and p=0.042 respectively). The forelimb placing and beam balance tests showed a clear recovery trend but did not reach statistical significance. While IGF-1 does not significantly cross the blood-brain barrier following traditional peripheral routes of administration, it can be delivered to the brain directly from the nasal cavity following intranasal administration. IN IGF-1 reduced both infarct volume and cerebral edema and also significantly reduced neurologic deficits following MCAO. Our study indicates IN delivery of IGF-1 holds significant promise as a noninvasive and efficacious method for treating stroke.
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Hu, Kang, and Gaojie Qu. "Effects of Bone Marrow Mesenchymal Stem Cells on Neurological Function, Transforming Growth Factor Beta 1 and Nogo-A Expression in Stroke Rats." Journal of Biomaterials and Tissue Engineering 11, no. 12 (December 1, 2021): 2466–71. http://dx.doi.org/10.1166/jbt.2021.2830.
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To investigate BMSCs’ effect on neurological function, TGF-β1 and Nogo-A expression in stroke rats. Rats were assigned into sham operation group, ischemia group (MACO rat model) and BMSCs group (BMSCs transplantation) followed by analysis of neurological function, brain pathological changes, cerebral infarction volume, TGF-β1 and Nogo-A level by Western blot. Compared with sham operation group, the score of rats was significantly elevated in ischemic group and decreased in BMSCs group (P <0.05). Compared with sham-operated group, ischemic group showed significantly increased cerebral infarction area (P <0.05) and BMSCs group had a significant decreased water level and brain infarct volume (P < 0.05). Compared with sham-operated group, ischemic group had more edema in the nerve cells with serious vacuole, uneven cytoplasm staining and reduced number of neurons, which were all significantly improved in BMSCs group. Compared to sham group, ischemic group showed significantly reduced TGF-β1 and increased Nogo-A level (P <0.05), which were all reversed in BMSCs group (P <0.05). BMSCs transplantation can significantly improve the nerve function of stroke rats, promote TGF-β1 secretion and inhibit Nogo-A expression.
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Doğgan, Aclan, A. Muralikrishna Rao, Mustafa K. Başkaya, V. L. Raghavendra Rao, Jane Rastl, David Donaldson, and Robert J. Dempsey. "Effects of ifenprodil, a polyamine site NMDA receptor antagonist, on reperfusion injury after transient focal cerebral ischemia." Journal of Neurosurgery 87, no. 6 (December 1997): 921–26. http://dx.doi.org/10.3171/jns.1997.87.6.0921.
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✓ Polyamines and N-methyl-d-aspartate (NMDA) receptors are both thought to play an important role in secondary neuronal injury after cerebral ischemia. Ifenprodil, known as a noncompetitive inhibitor of polyamine sites at the NMDA receptor, was studied after transient focal cerebral ischemia occurred. Spontaneously hypertensive male rats, each weighing between 250 and 350 g, underwent 3 hours of tandem middle cerebral artery (MCA) and common carotid artery occlusion followed by reperfusion for a period of 3 hours or 21 hours. Intravenous ifenprodil (10 µg/kg/minute) or saline infusion was started immediately after the onset of MCA occlusion and continued throughout the ischemic period. Physiological parameters including blood pressure, blood gas levels, blood glucose, hemoglobin, and rectal and temporal muscle temperatures were monitored. Six rats from each group were evaluated at 6 hours postocclusion for brain water content, an indicator of brain edema, and Evans blue dye extravasation for blood-brain barrier breakdown. Infarct volume was also measured in six rats from each group at 6 and 24 hours postocclusion. Ifenprodil treatment significantly reduced brain edema (82.5 ± 0.4% vs. 83.5 ± 0.4%, p < 0.05) and infarct volume (132 ± 14 mm3 vs. 168 ± 25 mm3, p < 0.05) compared with saline treatment, with no alterations in temporal muscle (brain) or rectal (body) temperature (35.9 ± 0.4°C vs. 36.2 ± 0.2°C; 37.7 ± 0.4°C vs. 37.6 ± 0.6°C; not significant). These results demonstrate that ifenprodil has neuroprotective properties after ischemia/reperfusion injury in the absence of hypothermia. This indicates that antagonists selective for the polyamine site of the NMDA receptors may be a viable treatment option and helps to explain some of the pathophysiological mechanisms involved in secondary injury after transient focal cerebral ischemia has occurred.
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Liang, Jia, Zhifeng Qi, Wenlan Liu, Peng Wang, Wenjuan Shi, Wen Dong, Xunming Ji, Yumin Luo, and Ke Jian Liu. "Normobaric Hyperoxia Slows Blood–Brain Barrier Damage and Expands the Therapeutic Time Window for Tissue-Type Plasminogen Activator Treatment in Cerebral Ischemia." Stroke 46, no. 5 (May 2015): 1344–51. http://dx.doi.org/10.1161/strokeaha.114.008599.
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Background and Purpose— Prolonged ischemia causes blood–brain barrier (BBB) damage and increases the incidence of neurovasculature complications secondary to reperfusion. Therefore, targeting ischemic BBB damage pathogenesis is critical to reducing neurovasculature complications and expanding the therapeutic time window of tissue-type plasminogen activator (tPA) thrombolysis. This study investigates whether increasing cerebral tissue P O 2 through normobaric hyperoxia (NBO) treatment will slow the progression of BBB damage and, thus, improve the outcome of delayed tPA treatment after cerebral ischemia. Methods— Rats were exposed to NBO (100% O 2 ) or normoxia (21% O 2 ) during 3-, 5-, or, 7-hour middle cerebral artery occlusion. Fifteen minutes before reperfusion, tPA was continuously infused to rats for 30 minutes. Neurological score, mortality rate, and BBB permeability were determined. Matrix metalloproteinase-9 was measured by gelatin zymography and tight junction proteins (occludin and cluadin-5) by Western blot in the isolated cerebral microvessels. Results— NBO slowed the progression of ischemic BBB damage pathogenesis, evidenced by reduced Evan blue leakage, smaller edema, and hemorrhagic volume in NBO-treated rats. NBO treatment reduced matrix metalloproteinase-9 induction and the loss of tight junction proteins in ischemic cerebral microvessels. NBO-afforded BBB protection was maintained during tPA reperfusion, resulting in improved neurological functions, significant reductions in brain edema, hemorrhagic volume, and mortality rate, even when tPA was given after prolonged ischemia (7 hours). Conclusions— Early NBO treatment slows ischemic BBB damage pathogenesis and significantly improves the outcome of delayed tPA treatment, providing new evidence supporting NBO as an effective adjunctive therapy to extend the time window of tPA thrombolysis for ischemic stroke.
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Kuhn, Frederick A., Sergio Gonzalez, Magdalena Rodriguez, Carlos Cuilty Siller, Venetia Zachariou, and Barry D. Goldstein. "Capsaicin's Effect on Rat Nasal Mucosa Substance P Release: Experimental Basis for Vasomotor Rhinitis Treatment." American Journal of Rhinology 11, no. 4 (July 1997): 313–16. http://dx.doi.org/10.2500/105065897781446649.
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Substance P (SP) is one of several neuropeptides found in nasal mucosa. It exists primarily in sensory afferent neurons, which are best demonstrated by immunohistochemical staining. These substance P-like immunoreactive (SPLI) nerve fibers are unmyelinated C fibers, which connect to the trigeminal ganglion and the spinal trigeminal nucleus. They are found around vessels and seromucinous glands in the submucosa. When the nasal mucosa receives a noxious stimulus, SP is released and acts orthodromically as a comediator of nasal pain, while antidromically it induces vasodilatation, plasma extravasation, mucosal edema, and rhinorrhea. Its antidromic effects have been implicated in vasomotor rhinitis and can be blocked by topical intranasal capsaicin application. Wolf and others have demonstrated in human subjects that vasomotor rhinitis can be blocked up to 1 year by a series of intranasal capsaicin applications. It has not yet been demonstrated that nasal mucous SP levels following noxious nasal stimulus change after intranasal capsaicin pretreatment. Consequently, a project was designed to determine whether intranasal capsaicin pretreatment would affect nasal substance P release measured in nasal secretion. Nasal secretion SP levels were measured before and after noxious nasal stimulus in controls and in capsaicin pretreated rats. The difference in measured nasal secretion SP levels were significant (p < 0.05).
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Wong, Simon S., Nina N. Sun, R. Clark Lantz, and Mark L. Witten. "Substance P and neutral endopeptidase in development of acute respiratory distress syndrome following fire smoke inhalation." American Journal of Physiology-Lung Cellular and Molecular Physiology 287, no. 4 (October 2004): L859—L866. http://dx.doi.org/10.1152/ajplung.00388.2003.
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To characterize the tachykininergic effects in fire smoke (FS)-induced acute respiratory distress syndrome (ARDS), we designed a series of studies in rats. Initially, 20 min of FS inhalation induced a significant increase of substance P (SP) in bronchoalveolar lavage fluid (BALF) at 1 h and persisted for 24 h after insult. Conversely, FS disrupted 51.4, 55.6, 46.3, and 43.0% enzymatic activity of neutral endopeptidase (NEP, a primary hydrolyzing enzyme for SP) 1, 6, 12, and 24 h after insult, respectively. Immunolabeling density of NEP in the airway epithelium largely disappeared 1 h after insult due to acute cell damage and shedding. These changes were also accompanied by extensive influx of albumin and granulocytes/lymphocytes in BALF. Furthermore, levels of BALF SP and tissue NEP activity dose dependently increased and decreased, respectively, following 0, low (10 min), and high (20 min) levels of FS inhalation. However, neither the time-course nor the dose-response study observed a significant change in the highest affinity neurokinin-1 receptor (NK-1R) for SP. Finally, treatment (10 mg/kg im) with SR-140333B, an NK-1R antagonist, significantly prevented 20-min FS-induced hypoxemia and pulmonary edema 24 h after insult. Further examination indicated that SR-140333B (1.0 or 10.0 mg/kg im) fully abolished early (1 h) plasma extravasation following FS. Collectively, these findings suggest that a combination of sustained SP and NEP inactivity induces an exaggerated neurogenic inflammation mediated by NK-1R, which may lead to an uncontrolled influx of protein-rich edema fluid and cells into the alveoli as a consequence of increased vascular permeability.
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Hong, Jin Young, Su Hee Kim, Yoojin Seo, Jooik Jeon, Ganchimeg Davaa, Soo Hyun Kim, and Jung Keun Hyun. "Self-assembling peptide gels promote angiogenesis and functional recovery after spinal cord injury in rats." Journal of Tissue Engineering 13 (January 2022): 204173142210864. http://dx.doi.org/10.1177/20417314221086491.
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Spinal cord injury (SCI) leads to disruption of the blood–spinal cord barrier, hemorrhage, and tissue edema, which impair blood circulation and induce ischemia. Angiogenesis after SCI is an important step in the repair of damaged tissues, and the extent of angiogenesis strongly correlates with the neural regeneration. Various biomaterials have been developed to promote angiogenesis signaling pathways, and angiogenic self-assembling peptides are useful for producing diverse supramolecular structures with tunable functionality. RADA16 (Ac-RARADADARARADADA-NH2), which forms nanofiber networks under physiological conditions, is a self-assembling peptide that can provide mechanical support for tissue regeneration and reportedly has diverse roles in wound healing. In this study, we applied an injectable form of RADA16 with or without the neuropeptide substance P to the contused spinal cords of rats and examined angiogenesis within the damaged spinal cord and subsequent functional improvement. Histological and immunohistochemical analyses revealed that the inflammatory cell population in the lesion cavity was decreased, the vessel number and density around the damaged spinal cord were increased, and the levels of neurofilaments within the lesion cavity were increased in SCI rats that received RADA16 and RADA16 with substance P (rats in the RADA16/SP group). Moreover, real-time PCR analysis of damaged spinal cord tissues showed that IL-10 expression was increased and that locomotor function (as assessed by the Basso, Beattie, and Bresnahan (BBB) scale and the horizontal ladder test) was significantly improved in the RADA16/SP group compared to the control group. Our findings indicate that RADA16 modified with substance P effectively stimulates angiogenesis within the damaged spinal cord and is a candidate agent for promoting functional recovery post-SCI.
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Carswell, H. V. O., A. F. Dominiczak, and I. M. Macrae. "Estrogen status affects sensitivity to focal cerebral ischemia in stroke-prone spontaneously hypertensive rats." American Journal of Physiology-Heart and Circulatory Physiology 278, no. 1 (January 1, 2000): H290—H294. http://dx.doi.org/10.1152/ajpheart.2000.278.1.h290.
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Estrogen treatment has been shown to reduce ischemic brain damage. Because endogenous estrogen levels fluctuate markedly during the estrous cycle, we investigated the effect of stage of estrous cycle on ischemic brain damage. Halothane anesthetized 3- to 5-mo-old female Wistar-Kyoto rats (WKY) and stroke-prone spontaneously hypertensive rats (SHRSP) in proestrus (high estradiol levels) or metestrus (low estradiol levels) underwent permanent middle cerebral artery occlusion. In SHRSP, infarct volume at 24 h postocclusion was 24% smaller in proestrus compared with metestrus [208.6 ± 9.5 mm3 ( n = 7) vs. 272.7 ± 23.8 mm3 ( n = 7), respectively, means ± SE; P = 0.0278, unpaired t-test]. In WKY, infarct volumes were similar in proestrus and metestrus [157.0 ± 5.4 mm3 ( n= 5) and 131.5 ± 16.5 mm3 ( n = 8), respectively; P = not significant (NS)]. Brain swelling (ipsilateral minus contralateral hemispheric volumes) was similar in proestrus and metestrus for SHRSP [138 ± 9 mm3 ( n = 6) and 136 ± 10 mm3 ( n = 7), respectively] and for WKY [103 ± 15 mm3 ( n = 5) and 90 ± 11 mm3 ( n = 8), respectively]. Thus the reduction in infarct size in SHRSP is caused by a true attenuation of the infarct volume and not simply by a reduction in brain edema.
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Huang, Z. Gao, Dong Xue, Hasneen Karbalai, Alastair M. Buchan, Z. Gao Huang, Dong Xue, and Edward Preston. "Biphasic Opening of the Blood-Brain Barrier Following Transient Focal Ischemia: Effects of Hypothermia." Canadian Journal of Neurological Sciences / Journal Canadien des Sciences Neurologiques 26, no. 4 (November 1999): 298–304. http://dx.doi.org/10.1017/s0317167100000421.
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Objective:Tracer constants (Ki) for blood-to-brain diffusion of sucrose were measured in the rat to profile the time course of blood-brain barrier injury after temporary focal ischemia, and to determine the influence of post-ischemic hypothermia.Methods:Spontaneously hypertensive rats were subjected to transient (2 hours) clip occlusion of the right middle cerebral artery. Reperfusion times ranged from 1.5 min to 46 hours, and i.v. 3H-sucrose was circulated for 30 min prior to each time point (1h, 4h, 22h, and 46h; n=5-7 per time point). Ki was calculated from the ratio of parenchymal tracer uptake and the time-integrated plasma concentration. Additional groups of rats (n=7-8) were maintained either normothermic (37.5oC) or hypothermic (32.5oC or 28.5oC) for the first 6 hours of reperfusion, and Ki was measured at 46 hours.Results:Rats injected after 1.5 - 2 min exhibited a 10-fold increase in Ki for cortical regions supplied by the right middle cerebral artery (p<0.01). This barrier opening had closed within 1 to 4 hours post-reperfusion. By 22 hours, the blood-brain barrier had re-opened, with further opening 22 and 46 hours (p<0.01), resulting in edema. Whole body hypothermia (28oC-29oC) during the first six hours of reperfusion prevented opening, reducing Ki by over 50% (p<0.05).Conclusion:Transient middle cerebral artery occlusion evokes a marked biphasic opening of the cortical blood-brain barrier, the second phase of which causes vasogenic edema. Hypothermic treatment reduced infarct volume and the late opening of the blood-brain barrier. This opening of the blood-brain barrier may enhance delivery of low permeability neuroprotective agents.
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Karibe, Hiroshi, Gregory J. Zarow, Steven H. Graham, and Philip R. Weinstein. "Mild Intraischemic Hypothermia Reduces Postischemic Hyperperfusion, Delayed Postischemic Hypoperfusion, Blood-Brain Barrier Disruption, Brain Edema, and Neuronal Damage Volume after Temporary Focal Cerebral Ischemia in Rats." Journal of Cerebral Blood Flow & Metabolism 14, no. 4 (July 1994): 620–27. http://dx.doi.org/10.1038/jcbfm.1994.77.
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Mild to moderate hypothermia (30–33°C) reduces brain injury after brief (<2-h) periods of focal ischemia, but its effectiveness in prolonged temporary ischemia is not fully understood. Thirty-two Sprague–Dawley rats anesthetized with 1.5% isoflurane underwent 3 h of middle cerebral artery occlusion under hypothermic (33°C) or normothermic (37°C) conditions followed by 3 or 21 h of reperfusion under normothermic conditions ( n = 8/group). Laser–Doppler estimates of cortical blood flow showed that intraischemic hypothermia reduced both postischemic hyperperfusion ( p ≤ 0.01) and postischemic delayed hypoperfusion ( p ≤ 0.01). Hypothermia reduced the extent of blood-brain barrier (BBB) disruption as estimated from the extravasation of Evans blue dye at 6 h after the onset of ischemia ( p ≤ 0.01). Hypothermia also reduced the volume of both brain edema ( p ≤ 0.01) and neuronal damage ( p ≤ 0.01) as estimated from Nissl-stained slides at both 6 and 24 h after the onset of ischemia. These results demonstrate that mild intraischemic hypothermia reduces tissue injury after prolonged temporary ischemia, possibly by attenuating postischemic blood flow disturbances and by reducing vasogenic edema resulting from BBB disruption.