Статті в журналах: "Ischemic-like damage"

1

Skvortsova, V. I., M. Kh Shurdumova, and E. V. Konstantinova. "The Significance of Toll-Like Receptors in the Development of Ischemic Damage." Neuroscience and Behavioral Physiology 41, no. 5 (May 25, 2011): 548–53. http://dx.doi.org/10.1007/s11055-011-9453-2.

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Patel, Hemanshu, Cissy Yong, Ali Navi, Sidney G. Shaw, Xu Shiwen, David Abraham, Daryll M. Baker, and Janice CS Tsui. "Toll-like receptors 2 and 6 mediate apoptosis and inflammation in ischemic skeletal myotubes." Vascular Medicine 24, no. 4 (May 14, 2019): 295–305. http://dx.doi.org/10.1177/1358863x19843180.

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Critical limb ischemia (CLI) is associated with skeletal muscle damage. However, the pathophysiology of the muscle damage is poorly understood. Toll-like receptors (TLR) have been attributed to play a role in ischemia-induced tissue damage but their role in skeletal muscle damage in CLI is unknown. TLR2 and TLR6 expression was found to be upregulated in skeletal muscle of patients with CLI. In vitro, ischemia led to upregulation of TLR2 and TLR6 by myotubes, and activation of the downstream TLR signaling pathway. Ischemia-induced activation of the TLR signaling pathway led to secretion of the pro-inflammatory cytokine interleukin-6 and muscle apoptosis, which were abrogated by neutralising TLR2 and TLR6 antibodies. Our study demonstrates that TLR2 and TLR6 are upregulated in ischemic muscle and play a role in ischemia-induced muscle damage. Thus, manipulating the TLR pathway locally may be of potential therapeutic benefit.

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Packard, Amy E. B., Jason C. Hedges, Frances R. Bahjat, Susan L. Stevens, Michael J. Conlin, Andres M. Salazar, and Mary P. Stenzel-Poore. "Poly-IC Preconditioning Protects against Cerebral and Renal Ischemia-Reperfusion Injury." Journal of Cerebral Blood Flow & Metabolism 32, no. 2 (November 16, 2011): 242–47. http://dx.doi.org/10.1038/jcbfm.2011.160.

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Preconditioning induces ischemic tolerance, which confers robust protection against ischemic damage. We show marked protection with polyinosinic polycytidylic acid (poly-IC) preconditioning in three models of murine ischemia-reperfusion injury. Poly-IC preconditioning induced protection against ischemia modeled in vitro in brain cortical cells and in vivo in models of brain ischemia and renal ischemia. Further, unlike other Toll-like receptor (TLR) ligands, which generally induce significant inflammatory responses, poly-IC elicits only modest systemic inflammation. Results show that poly-IC is a new powerful prophylactic treatment that offers promise as a clinical therapeutic strategy to minimize damage in patient populations at risk of ischemic injury.

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Stevens, Susan L., Thomas MP Ciesielski, Brenda J. Marsh, Tao Yang, Delfina S. Homen, Jo-Lynn Boule, Nikola S. Lessov, Roger P. Simon, and Mary P. Stenzel-Poore. "Toll-Like Receptor 9: A New Target of Ischemic Preconditioning in the Brain." Journal of Cerebral Blood Flow & Metabolism 28, no. 5 (January 9, 2008): 1040–47. http://dx.doi.org/10.1038/sj.jcbfm.9600606.

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Preconditioning with lipopolysaccharide (LPS), a toll-like receptor 4 (TLR4) ligand, provides neuroprotection against subsequent cerebral ischemic brain injury, through a tumor necrosis factor (TNF)α-dependent process. Here, we report the first evidence that another TLR, TLR9, can induce neuroprotection. We show that the TLR9 ligand CpG oligodeoxynucleotide (ODN) can serve as a potent preconditioning stimulus and provide protection against ischemic brain injury. Our studies show that systemic administration of CpG ODN 1826 in advance of brain ischemia (middle cerebral artery occlusion (MCAO)) reduces ischemic damage up to 60% in a dose- and time-dependent manner. We also offer evidence that CpG ODN preconditioning can provide direct protection to cells of the central nervous system, as we have found marked neuroprotection in modeled ischemia in vitro. Finally, we show that CpG preconditioning significantly increases serum TNFα levels before MCAO and that TNFα is required for subsequent reduction in damage, as mice lacking TNFα are not protected against ischemic injury by CpG preconditioning. Our studies show that preconditioning with a TLR9 ligand induces neuroprotection against ischemic injury through a mechanism that shares common elements with LPS preconditioning via TLR4.

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Song, Ying, Meng Li, Ji-cheng Li, and Er-qing Wei. "Edaravone protects PC12 cells from ischemic-like injury via attenuating the damage to mitochondria." Journal of Zhejiang University SCIENCE B 7, no. 9 (September 2006): 749–56. http://dx.doi.org/10.1631/jzus.2006.b0749.

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6

Ryu, Ji Hyeon, Yeonye Kim, Min Jae Kim, Jisu Park, Ji Won Kim, Hye Sook Park, Young Sil Kim, Hwa Kyoung Shin та Yong-Il Shin. "Membrane-Free Stem Cell Extract Enhances Blood–Brain Barrier Integrity by Suppressing NF-κB-Mediated Activation of NLRP3 Inflammasome in Mice with Ischemic Stroke". Life 12, № 4 (29 березня 2022): 503. http://dx.doi.org/10.3390/life12040503.

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Membrane-free stem cell extract (MFSCE) of human adipose tissues possesses various biological activities. However, the effects of MFSCE on blood–brain barrier dysfunction and brain damage are unknown. In this study, we determined the role of MFSCE in an ischemic stroke mouse model. Mice were treated with MFSCE once daily for 4 days and 1 h before ischemic damage. Experimental ischemia was induced by photothrombosis. Pretreatment with MFSCE reduced infarct volume and edema and improved neurological, as well as motor functions. Evans blue leakage and water content in the brain tissue were reduced by MFSCE pretreatment relative to those in the vehicle group. MFSCE increased the expression of the tight junction proteins zonula occludens 1 and claudin-5, as well as vascular endothelial-cadherin, but decreased that of matrix metalloproteinase 9. Notably, MFSCE treatment decreased cell death and the level of NOD-like receptor protein 3 inflammasome, consistent with the downregulated expression of the pro-inflammatory cytokines interleukin (IL)-1β and IL-18 in the ischemic brain. These effects might have occurred via the suppression of the expression of Toll-like receptor 4 and activation of nuclear factor-κB. The results highlighted the potential of MFSCE treatment as a novel and preventive strategy for patients at a high risk of ischemic stroke.

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Fan, Hongguang, Litao Li, Xiangjian Zhang, Ying Liu, Chenhui Yang, Yi Yang та Jing Yin. "Oxymatrine Downregulates TLR4, TLR2, MyD88, and NF-κB and Protects Rat Brains against Focal Ischemia". Mediators of Inflammation 2009 (2009): 1–10. http://dx.doi.org/10.1155/2009/704706.

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Inflammatory damage plays an important role in cerebral ischemic pathogenesis and may represent a target for treatment. Toll-like receptor-4 (TLR4), toll-like receptor-2 (TLR2), myeloid differentiation factor 88 (MyD88), and nuclear factor kappa-B (NF-κB) have been linked to inflammatory reactions. Our previous studies have proved that oxymatrine (OMT) protected ischemic brain injury and this effect may be through the decreasing of NF-κB expression. However, little is known regarding the mechanism of OMT in the acute phase of ischemic stroke. We therefore investigated the OMT's potential neuroprotective role and the underlying mechanisms. Male, Sprague-Dawley rats were randomly divided into sham, saline and OMT treatment groups. We used a middle cerebral artery occlusion (MCAO) model and administered OMT intraperitoneally immediately after cerebral ischemia and once daily on the following days. At time points after MCAO, brain water content and infarct size were measured. Immunohistochemistry and RT-PCR were used to analyse the expression of TLR4, TLR2, MyD88, and NF-κB at gene and protein level in ischemic brain tissue. The result indicated that OMT protected the brain from damage caused by MCAO; this effect may be through downregulation of the TLR4, TLR2, MyD88, and NF-κB.

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8

Yang, Qing-Wu, Feng-Lin Lu, Yu Zhou, Lin Wang, Qi Zhong, Sen Lin, Jing Xiang, Jing-Cheng Li, Chuan-Qing Fang, and Jing-Zhou Wang. "HMBG1 Mediates Ischemia—Reperfusion Injury by TRIF-Adaptor Independent Toll-Like Receptor 4 Signaling." Journal of Cerebral Blood Flow & Metabolism 31, no. 2 (August 11, 2010): 593–605. http://dx.doi.org/10.1038/jcbfm.2010.129.

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High-mobility group protein box-1 (HMGB1) has recently been recognized as a novel candidate in a specific upstream pathway promoting inflammation after brain ischemia. However, its downstream pathway and underlying mechanism have yet to be elucidated. The HMGB1 level in the acute cerebral infarct (ACI) group was significantly increased compared with that of control group, and correlated with the severity of neurologic impairment of ACI patients. Further, recombinant human HMGB1 (rhHMGB1) had no effect on microglia derived from mice lacking the Toll-like receptor 4 (TLR4−/–). Intracerebroventricular injection of rhHMGB1 in TLR4+/+ mice cause significantly more injury after cerebral ischemia–reperfusion than control group. But, TLR4−/– mice administered with rhHMGB1 showed moderate impairment after ischemia–reperfusion than TLR4+/+ mice. To determine the potential downstream signaling of HMGB1/TLR4 in cerebral ischemic injury, we used the ischemic–reperfusion model with Toll/interleukin-1 receptor domain-containing adaptor-inducing interferon-β knockout mice (TRIF−/–) and evaluated the activity and expression of TRIF pathway-related kinases. The results suggest that the TRIF pathway is not likely to be involved in TLR4-mediated ischemia brain injury. Finally, we found that TLR4 expressed by immigrant macrophages was involved in the development of ischemic brain damage. These results suggest that HMBG1 mediates ischemia–reperfusion injury by TRIF-adaptor independent Toll-like receptor 4 signaling. The TLR4 expressed by immigrant macrophages may be involved in the development of ischemic brain damage.

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9

Dewar, Deborah, Suzanne M. Underhill, and Mark P. Goldberg. "Oligodendrocytes and Ischemic Brain Injury." Journal of Cerebral Blood Flow & Metabolism 23, no. 3 (March 2003): 263–74. http://dx.doi.org/10.1097/01.wcb.0000053472.41007.f9.

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Oligodendrocytes, myelin-forming glial cells of the central nervous system, are vulnerable to damage in a variety of neurologic diseases. Much is known of primary myelin injury, which occurs in settings of genetic dysmyelination or demyelinating disease. There is growing awareness that oligodendrocytes are also targets of injury in acute ischemia. Recognition of oligodendrocyte damage in animal models of ischemia requires attention to their distinct histologic features or use of specific immunocytochemical markers. Like neurons, oligodendrocytes are highly sensitive to injury by oxidative stress, excitatory amino acids, trophic factor deprivation, and activation of apoptotic pathways. Understanding mechanisms of oligodendrocyte death may suggest new therapeutic strategies to preserve or restore white matter function and structure after ischemic insults.

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10

Danakas, Alexandra M., Bushra G. Fazili, and Aaron R. Huber. "Mass-Forming Ischemic Colitis: A Potential Mimicker of Malignancy." Case Reports in Pathology 2019 (March 17, 2019): 1–3. http://dx.doi.org/10.1155/2019/8927872.

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Ischemic colitis (IC) results from reduced colonic vascular perfusion, accounting for 50-60% of all gastrointestinal ischemic episodes. IC leads to mucosal damage with clinical symptom severity developing based on the duration and extent of colonic injury. In rare cases IC may form a mass-like lesion mimicking malignancy. Here we present the case of a 55-year-old female with hematochezia and diarrhea, who on workup was found to have a mass-like lesion at the ileocecal valve. Multiple biopsies demonstrated ischemic change and mucosal injury without evidence of dysplasia or carcinoma. Two months later on follow-up imaging, after supportive treatment the lesion was completely resolved. It is critical for gastroenterologists and pathologists to be aware of this variant of IC to avoid unnecessary surgical procedures and treatment of patients.

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11

Smirkin, Anna, Hiroaki Matsumoto, Hisaaki Takahashi, Akihiro Inoue, Masahiko Tagawa, Shiro Ohue, Hideaki Watanabe, et al. "Iba1+/NG2+ Macrophage-Like Cells Expressing a Variety of Neuroprotective Factors Ameliorate Ischemic Damage of the Brain." Journal of Cerebral Blood Flow & Metabolism 30, no. 3 (October 28, 2009): 603–15. http://dx.doi.org/10.1038/jcbfm.2009.233.

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In a transient 90-min middle cerebral artery occlusion (MCAO) model of rats, a large ischemic lesion is formed where macrophage-like cells massively accumulate, many of which express a macrophage marker, Iba1, and an oligodendrocyte progenitor cell marker, NG2 chondroitin sulfate proteoglycan (NG2); therefore, the cells were termed BINCs (Brain Iba1+/NG2+Cells). A bone marrow transplantation experiment using green-fluorescent protein-transgenic rats showed that BINCs were derived from bone marrow. 5-Fluorouracil (5FU) injection at 2 days post reperfusion (2 dpr) markedly reduced the number of BINCs at 7 dpr, causing enlargement of necrotic volumes and frequent death of the rats. When isolated BINCs were transplanted into 5FU-aggravated ischemic lesion, the volume of the lesion was much reduced. Quantitative real-time RT-PCR showed that BINCs expressed mRNAs encoding bFGF, BMP2, BMP4, BMP7, GDNF, HGF, IGF-1, PDGF-A, and VEGF. In particular, BINCs expressed IGF-1 mRNA at a very high level. Immunohistochemical staining showed that IGF-1-expressing BINCs were found not only in rat but also human ischemic brain lesions. These results suggest that bone marrow-derived BINCs play a beneficial role in ischemic brain lesions, at least in part, through secretion of neuroprotective factors.

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12

Bahjat, Frances Rena, Rebecca L. Williams-Karnesky, Steven G. Kohama, G. Alexander West, Kristian P. Doyle, Maxwell D. Spector, Theodore R. Hobbs, and Mary P. Stenzel-Poore. "Proof of Concept: Pharmacological Preconditioning with a Toll-like Receptor Agonist Protects against Cerebrovascular Injury in a Primate Model of Stroke." Journal of Cerebral Blood Flow & Metabolism 31, no. 5 (February 2, 2011): 1229–42. http://dx.doi.org/10.1038/jcbfm.2011.6.

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Cerebral ischemic injury is a significant portion of the burden of disease in developed countries; rates of mortality are high and the costs associated with morbidity are enormous. Recent therapeutic approaches have aimed at mitigating the extent of damage and/or promoting repair once injury has occurred. Often, patients at high risk of ischemic injury can be identified in advance and targeted for antecedent neuroprotective therapy. Agents that stimulate the innate pattern recognition receptor, Toll-like receptor 9, have been shown to induce tolerance (precondition) to ischemic brain injury in a mouse model of stroke. Here, we demonstrate for the first time that pharmacological preconditioning against cerebrovascular ischemic injury is also possible in a nonhuman primate model of stroke in the rhesus macaque. The model of stroke used is a minimally invasive transient vascular occlusion, resulting in brain damage that is primarily localized to the cortex and as such, represents a model with substantial clinical relevance. Finally, K-type (also referred to as B-type) cytosine-guanine-rich DNA oligonucleotides, the class of agents employed in this study, are currently in use in human clinical trials, underscoring the feasibility of this treatment in patients at risk of cerebral ischemia.

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13

Rohde, David, Christoph Schön, Melanie Boerries, Ieva Didrihsone, Julia Ritterhoff, Katharina F. Kubatzky, Mirko Völkers, et al. "S100A1 is released from ischemic cardiomyocytes and signals myocardial damage via Toll‐like receptor 4." EMBO Molecular Medicine 6, no. 6 (May 15, 2014): 778–94. http://dx.doi.org/10.15252/emmm.201303498.

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14

Hayashi, Takeshi, Atsushi Saito, Shuzo Okuno, Michel Ferrand-Drake, Robert L. Dodd, Tatsuro Nishi, Carolina M. Maier, Hiroyuki Kinouchi, and Pak H. Chan. "Oxidative Damage to the Endoplasmic Reticulum is Implicated in Ischemic Neuronal Cell Death." Journal of Cerebral Blood Flow & Metabolism 23, no. 10 (October 2003): 1117–28. http://dx.doi.org/10.1097/01.wcb.0000089600.87125.ad.

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The endoplasmic reticulum (ER), which plays important roles in apoptosis, is susceptible to oxidative stress. Because reactive oxygen species (ROS) are robustly produced in the ischemic brain, ER damage by ROS may be implicated in ischemic neuronal cell death. We induced global brain ischemia on wild-type and copper/zinc superoxide dismutase (SOD1) transgenic rats and compared ER stress and neuronal damage. Phosphorylated forms of eukaryotic initiation factor 2α (eIF2α) and RNA-dependent protein kinase-like ER eIF2α kinase (PERK), both of which play active roles in apoptosis, were increased in hippocampal CA1 neurons after ischemia but to a lesser degree in the transgenic animals. This finding, together with the finding that the transgenic animals showed decreased neuronal degeneration, indicates that oxidative ER damage is involved in ischemic neuronal cell death. To elucidate the mechanisms of ER damage by ROS, we analyzed glucose-regulated protein 78 (GRP78) binding with PERK and oxidative ER protein modification. The proteins were oxidatively modified and stagnated in the ER lumen, and GRP78 was detached from PERK by ischemia, all of which were attenuated by SOD1 overexpression. We propose that ROS attack and modify ER proteins and elicit ER stress response, which results in neuronal cell death.

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Dong, Yupeng, Yoshitaka Kimura, and Nobuo Yaegashi. "Amniotic LPS-Induced Apoptosis in the Fetal Brain Is Suppressed by Vaginal LPS Preconditioning but Is Promoted by Continuous Ischemic Reperfusion." International Journal of Molecular Sciences 23, no. 3 (February 4, 2022): 1787. http://dx.doi.org/10.3390/ijms23031787.

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Chorioamnionitis (CAM) is an increasingly common disease affecting pregnant women which derives from bacterial vaginosis. In different clinical cases, it has been shown that CAM can cause multiple risk factors for fetal brain damage, such as infection, and intra-uterine asphyxia. However, the molecular mechanism remains unknown. In this study, we established a novel CAM mouse model by exposing pregnant mice to a combination of three risk factors: vaginal lipopolysaccharides (LPS), amniotic LPS, and ischemic reperfusion. We found amniotic LPS caused Parkinson’s disease-like fetal brain damage, in a dose and time-dependent manner. Moreover, the mechanism of this fetal brain damage is apoptosis induced by amniotic LPS but it was inhibited by being pretreated with a vaginal LPS challenge before amniotic LPS injection. In contrast, amniotic LPS with continuous ischemic reperfusion caused a higher level of apoptotic cell death than amniotic LPS alone. In particular, a potential neuroprotective biomarker phosphorylation (p)-CREB (ser133) appeared in only vaginal LPS preconditioned before amniotic LPS, whereas ischemic reperfusion triggered IKK phosphorylation after amniotic LPS. Despite the need for many future investigations, this study also discussed a developed understanding of the molecular mechanism of how these phenotypes occurred.

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Mahaling, Binapani, Shermaine W. Y. Low, Molly Beck, Devesh Kumar, Simrah Ahmed, Thomas B. Connor, Baseer Ahmad, and Shyam S. Chaurasia. "Damage-Associated Molecular Patterns (DAMPs) in Retinal Disorders." International Journal of Molecular Sciences 23, no. 5 (February 26, 2022): 2591. http://dx.doi.org/10.3390/ijms23052591.

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Damage-associated molecular patterns (DAMPs) are endogenous danger molecules released from the extracellular and intracellular space of damaged tissue or dead cells. Recent evidence indicates that DAMPs are associated with the sterile inflammation caused by aging, increased ocular pressure, high glucose, oxidative stress, ischemia, mechanical trauma, stress, or environmental conditions, in retinal diseases. DAMPs activate the innate immune system, suggesting their role to be protective, but may promote pathological inflammation and angiogenesis in response to the chronic insult or injury. DAMPs are recognized by specialized innate immune receptors, such as receptors for advanced glycation end products (RAGE), toll-like receptors (TLRs) and the NOD-like receptor family (NLRs), and purine receptor 7 (P2X7), in systemic diseases. However, studies describing the role of DAMPs in retinal disorders are meager. Here, we extensively reviewed the role of DAMPs in retinal disorders, including endophthalmitis, uveitis, glaucoma, ocular cancer, ischemic retinopathies, diabetic retinopathy, age-related macular degeneration, rhegmatogenous retinal detachment, proliferative vitreoretinopathy, and inherited retinal disorders. Finally, we discussed DAMPs as biomarkers, therapeutic targets, and therapeutic agents for retinal disorders.

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17

Kübler, Matthias, Sebastian Beck, Silvia Fischer, Philipp Götz, Konda Kumaraswami, Hellen Ishikawa-Ankerhold, Manuel Lasch, and Elisabeth Deindl. "Absence of Cold-Inducible RNA-Binding Protein (CIRP) Promotes Angiogenesis and Regeneration of Ischemic Tissue by Inducing M2-Like Macrophage Polarization." Biomedicines 9, no. 4 (April 7, 2021): 395. http://dx.doi.org/10.3390/biomedicines9040395.

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Cold-inducible RNA-binding protein (CIRP) is an intracellular RNA-chaperone and extracellular promoter of inflammation, which is increasingly expressed and released under conditions of hypoxia and cold stress. The functional relevance of CIRP for angiogenesis and regeneration of ischemic muscle tissue has never been investigated and is the topic of the present study. We investigated the role of CIRP employing CIRP deficient mice along with a hindlimb model of ischemia-induced angiogenesis. 1 and 7 days after femoral artery ligation or sham operation, gastrocnemius muscles of CIRP-deficient and wildtype mice were isolated and processed for (immuno-) histological analyses. CIRP deficient mice showed decreased ischemic tissue damage as evidenced by Hematoxylin and Eosin staining, whereas angiogenesis was enhanced as demonstrated by increased capillary/muscle fiber ratio and number of proliferating endothelial (CD31+/BrdU+) cells on day 7 after surgery. Moreover, CIRP deficiency resulted in a reduction of total leukocyte count (CD45+), neutrophils (myeloperoxidase, MPO+), neutrophil extracellular traps (NETs) (MPO+/CitH3+), and inflammatory M1-like polarized macrophages (CD68+/MRC1-), whereas the number of tissue regenerating M2-like polarized macrophages (CD68+/MRC1-) was increased in ischemic tissue samples. In summary, we show that the absence of CIRP ameliorates angiogenesis and regeneration of ischemic muscle tissue, most likely by influencing macrophage polarization in direction to regenerative M2-like macrophages.

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Mohamed, Doaa I., Samar F. Ezzat, Wael M. Elayat, Omnyah A. El-Kharashi, Hanaa F. Abd El-Kareem, Hebatallah H. Abo Nahas, Basel A. Abdel-Wahab, et al. "Hepatoprotective Role of Carvedilol against Ischemic Hepatitis Associated with Acute Heart Failure via Targeting miRNA-17 and Mitochondrial Dynamics-Related Proteins: An In Vivo and In Silico Study." Pharmaceuticals 15, no. 7 (July 5, 2022): 832. http://dx.doi.org/10.3390/ph15070832.

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Acute heart failure (AHF) is one of the most common diseases in old age that can lead to mortality. Systemic hypoperfusion is associated with hepatic ischemia–reperfusion injury, which may be irreversible. Ischemic hepatitis due to AHF has been linked to the pathogenesis of liver damage. In the present study, we extensively investigated the role of mitochondrial dynamics-related proteins and their epigenetic regulation in ischemic liver injury following AHF and explored the possible hepatoprotective role of carvedilol. The biochemical analysis revealed that the ischemic liver injury following AHF significantly elevated the activity of alanine aminotransferase (ALT), aspartate aminotransferase (AST), and alkaline phosphatase (ALP) enzymes, the level of total and direct bilirubin, and the expression of hepatic mitogen-activated protein kinase (MAPK), dynamin-1-like protein (DNM1L), and hepatic miRNA-17. At the same time, it significantly reduced the serum albumin level, the activity of hepatic superoxide dismutase (SOD), and the expression of mitochondrial peroxisome proliferator-activated receptor-1α (PGC-1α), and mitofusin 2 (Mtf2). The histological examination of the liver tissue revealed degenerated hepatocytes. Interestingly, administration of carvedilol either prior to or after isoprenaline-induced AHF significantly improved the liver function and reversed the deterioration effect of AHF-induced ischemic hepatitis, as demonstrated by biochemical, immunohistochemical, and histological analysis. Our results indicated that the hepatoprotective effect of carvedilol in ameliorating hepatic ischemic damage could be attributed to its ability to target the mitochondrial dynamics-related proteins (Mtf2, DNM1L and PGC-1α), but also their epigenetic regulator miRNA-17. To further explore the mode of action of carvedilol, we have investigated, in silico, the ability of carvedilol to target dynamin-1-like protein and mitochondrial dynamics protein (MID51). Our results revealed that carvedilol has a high binding affinity (−14.83 kcal/mol) toward the binding pocket of DNM1L protein. In conclusion, our study highlights the hepatoprotective pharmacological application of carvedilol to attenuate ischemic hepatitis associated with AHF.

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Feng, Lishuai, Chaoran Dou, Yuguo Xia, Benhao Li, Mengyao Zhao, Peng Yu, Yuanyi Zheng, et al. "Neutrophil-like Cell-Membrane-Coated Nanozyme Therapy for Ischemic Brain Damage and Long-Term Neurological Functional Recovery." ACS Nano 15, no. 2 (January 11, 2021): 2263–80. http://dx.doi.org/10.1021/acsnano.0c07973.

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Xing, Zhu, Tang Zhen, Fan Jie, Yu Jie, Liu Shiqi, Zhu Kaiyi, OuYang Zhicui, and Hei Mingyan. "Early Toll-like receptor 4 inhibition improves immune dysfunction in the hippocampus after hypoxic-ischemic brain damage." International Journal of Medical Sciences 19, no. 1 (2022): 142–51. http://dx.doi.org/10.7150/ijms.66494.

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Di Raimondo, Domenico, Giuliana Rizzo, Gaia Musiari, Antonino Tuttolomondo, and Antonio Pinto. "Role of Regular Physical Activity in Neuroprotection against Acute Ischemia." International Journal of Molecular Sciences 21, no. 23 (November 29, 2020): 9086. http://dx.doi.org/10.3390/ijms21239086.

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One of the major obstacles that prevents an effective therapeutic intervention against ischemic stroke is the lack of neuroprotective agents able to reduce neuronal damage; this results in frequent evolution towards a long-term disability with limited alternatives available to aid in recovery. Nevertheless, various treatment options have shown clinical efficacy. Neurotrophins such as brain-derived neurotrophic factor (BDNF), widely produced throughout the brain, but also in distant tissues such as the muscle, have demonstrated regenerative properties with the potential to restore damaged neural tissue. Neurotrophins play a significant role in both protection and recovery of function following neurological diseases such as ischemic stroke or traumatic brain injury. Unfortunately, the efficacy of exogenous administration of these neurotrophins is limited by rapid degradation with subsequent poor half-life and a lack of blood–brain-barrier permeability. Regular exercise seems to be a therapeutic approach able to induce the activation of several pathways related to the neurotrophins release. Exercise, furthermore, reduces the infarct volume in the ischemic brain and ameliorates motor function in animal models increasing astrocyte proliferation, inducing angiogenesis and reducing neuronal apoptosis and oxidative stress. One of the most critical issues is to identify the relationship between neurotrophins and myokines, newly discovered skeletal muscle-derived factors released during and after exercise able to exert several biological functions. Various myokines (e.g., Insulin-Like Growth Factor 1, Irisin) have recently shown their ability to protects against neuronal injury in cerebral ischemia models, suggesting that these substances may influence the degree of neuronal damage in part via inhibiting inflammatory signaling pathways. The aim of this narrative review is to examine the main experimental data available to date on the neuroprotective and anti-ischemic role of regular exercise, analyzing also the possible role played by neurotrophins and myokines.

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Joshi, I., and R. D. Andrew. "Imaging Anoxic Depolarization During Ischemia-Like Conditions in the Mouse Hemi-Brain Slice." Journal of Neurophysiology 85, no. 1 (January 1, 2001): 414–24. http://dx.doi.org/10.1152/jn.2001.85.1.414.

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Focal ischemia evokes a sudden loss of membrane potential in neurons and glia of the ischemic core termed the anoxic depolarization (AD). In metabolically compromised regions with partial blood flow, peri-infarct depolarizations (PIDs) further drain energy reserves, promoting acute and delayed neuronal damage. Visualizing and quantifying the AD and PIDs and their acute deleterious effects are difficult in the intact animal. In the present study, we imaged intrinsic optical signals to measure changes in light transmittance in the mouse coronal hemi-brain slice during AD generation. The AD was induced by oxygen/glucose deprivation (OGD) or by ouabain exposure. Potential neuroprotective strategies using glutamate receptor antagonists or reduced temperature were tested. Eight minutes of OGD ( n = 18 slices) or 4 min of 100 μM ouabain ( n = 14) induced a focal increase of increased light transmittance (LT) in neocortical layers II/III that expanded concentrically to form a wave front coursing through neocortex and independently through striatum. The front was coincident with a negative voltage shift in extracellular potential. Wherever the LT front (denoting cell swelling) propagated, a decrease in LT (denoting dendritic beading) followed in its wake. In addition the evoked field potential was permanently lost, indicating neuronal damage. Glutamate receptor antagonists did not block the onset and propagation of AD or the extent of irreversible damage post-AD. Lowering temperature to 25–30°C protected the tissue from OGD damage by inhibiting AD onset. This study shows that anoxic depolarization evoked by global ischemia-like conditions is a spreading process that is focally initiated at multiple sites in cortical and subcortical gray. The combined energy demands of O2/glucose deprivation and the AD greatly exacerbate neuronal damage. Glutamate receptor antagonists neither block the AD in the ischemic core nor, we propose, block recurrent PID arising close to the core.

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Götz, Philipp, Anna Braumandl, Matthias Kübler, Konda Kumaraswami, Hellen Ishikawa-Ankerhold, Manuel Lasch, and Elisabeth Deindl. "C3 Deficiency Leads to Increased Angiogenesis and Elevated Pro-Angiogenic Leukocyte Recruitment in Ischemic Muscle Tissue." International Journal of Molecular Sciences 22, no. 11 (May 28, 2021): 5800. http://dx.doi.org/10.3390/ijms22115800.

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The complement system is a potent inflammatory trigger, activator, and chemoattractant for leukocytes, which play a crucial role in promoting angiogenesis. However, little information is available about the influence of the complement system on angiogenesis in ischemic muscle tissue. To address this topic and analyze the impact of the complement system on angiogenesis, we induced muscle ischemia in complement factor C3 deficient (C3−/−) and wildtype control mice by femoral artery ligation (FAL). At 24 h and 7 days after FAL, we isolated the ischemic gastrocnemius muscles and investigated them by means of (immuno-)histological analyses. C3−/− mice showed elevated ischemic damage 7 days after FAL, as evidenced by H&E staining. In addition, angiogenesis was increased in C3−/− mice, as demonstrated by increased capillary/muscle fiber ratio and increased proliferating endothelial cells (CD31+/BrdU+). Moreover, our results showed that the total number of leukocytes (CD45+) was increased in C3−/− mice, which was based on an increased number of neutrophils (MPO+), neutrophil extracellular trap formation (MPO+/CitH3+), and macrophages (CD68+) displaying a shift toward an anti-inflammatory and pro-angiogenic M2-like polarized phenotype (CD68+/MRC1+). In summary, we show that the deficiency of complement factor C3 increased neutrophil and M2-like polarized macrophage accumulation in ischemic muscle tissue, contributing to angiogenesis.

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24

Nighoghossian, Norbert, Michel Ovize, Nathan Mewton, Elodie Ong, and Tae-Hee Cho. "Cyclosporine A, a Potential Therapy of Ischemic Reperfusion Injury. A Common History for Heart and Brain." Cerebrovascular Diseases 42, no. 5-6 (2016): 309–18. http://dx.doi.org/10.1159/000446850.

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Background: Ischemic stroke (IS) and acute myocardial infarction require emergency reperfusion tissue in order to improve functional outcome. Intra-arterial thrombectomy recently showed very encouraging improvement in IS patients' outcome. However, endovascular methods enhancing reperfusion may expose patients to increase in ischemic reperfusion injury. Experimental evidence indicates that brain ischemic reperfusion injury may be attenuated by ischemic pre- and postconditioning. The opening of mitochondrial permeability transition pore plays a critical role in the onset of reperfusion damage. This mechanism can be inhibited by immunosuppressive drugs like cyclosporine A (CsA). Summary: In this review, we present existing experimental and clinical data suggesting that conditioning interventions may prevent brain ischemic reperfusion injury and future challenge for neuroprotection by CsA in acute IS. Key Messages: The concept of conditioning has been recently investigated clinically but to a lesser extent in the realm of IS. Recent experimental and phase II clinical research has suggested potential neuroprotective properties of cyclosporine; however, further larger clinical trials are needed to demonstrate that CsA improves clinical outcome in acute IS patients.

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25

Puleo, Maria Grazia, Salvatore Miceli, Tiziana Di Chiara, Giuseppina Maria Pizzo, Vittoriano Della Corte, Irene Simonetta, Antonio Pinto, and Antonino Tuttolomondo. "Molecular Mechanisms of Inflammasome in Ischemic Stroke Pathogenesis." Pharmaceuticals 15, no. 10 (September 21, 2022): 1168. http://dx.doi.org/10.3390/ph15101168.

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Ischemic stroke (also called cerebral ischemia) is one of the leading causes of death and severe disability worldwide. NLR inflammasomes play a crucial role in sensing cell damage in response to a harmful stimuli and modulating the inflammatory response, promoting the release of pro-inflammatory cytokines such as IL-18 and IL-1β following ischemic injury. Therefore, a neuroprotective effect is achieved by inhibiting the expression, assembly, and secretion of inflammasomes, thus limiting the extent of brain detriment and neurological sequelae. This review aims to illustrate the molecular characteristics, expression levels, and assembly of NLRP3 (nucleotide-binding oligomerization domain-like receptor [NLR] family pyrin-domain-containing 3) inflammasome, the most studied in the literature, in order to discover promising therapeutic implications. In addition, we provide some information regarding the contribution of NLRP1, NLRP2, and NLRC4 inflammasomes to ischemic stroke pathogenesis, highlighting potential therapeutic strategies that require further study.

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26

Buffon, Antonino, Stefano Rigattieri, Stefano A. Santini, Vito Ramazzotti, Filippo Crea, Bruno Giardina, and Attilio Maseri. "Myocardial ischemia-reperfusion damage after pacing-induced tachycardia in patients with cardiac syndrome X." American Journal of Physiology-Heart and Circulatory Physiology 279, no. 6 (December 1, 2000): H2627—H2633. http://dx.doi.org/10.1152/ajpheart.2000.279.6.h2627.

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The presence of myocardial ischemia in syndrome X (chest pain, “ischemia-like” electrocardiogram changes, and normal coronary angiograms) is uncertain possibly because, when focally distributed, it may not cause contractile dysfunction or lactate production. We measured lipid hydroperoxides (ROOHs) and conjugated dienes (CDs), two sensitive, independent markers of ischemia-reperfusion oxidative stress, in paired aortic and great cardiac vein blood samples before and after pacing-induced tachycardia in nine patients with syndrome X. Diagnostic ischemic S-T segment changes during pacing were followed by a consistent increase in ROOH and CD levels in the great cardiac vein (from 4.83 ± 1.18 μmol/l at baseline to 7.88 ± 1.12 μmol/l and from 0.038 ± 0.002 to 0.051 ± 0.003 arbitrary units, respectively, P < 0.01). In controls, ROOH and CD levels did not change after pacing. The large postpacing cardiac release of lipid peroxidation products, consistently observed in all patients and similar to that previously observed after ischemia caused by percutaneous transluminal coronary angioplasty, is consistent with an ischemic origin of syndrome X.

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Bosley, Thomas M., Ibrahim A. Alorainy, Darren T. Oystreck, Ali M. Hellani, Mohammed Z. Seidahmed, Mohamed El Faki Osman, Mohamed A. Sabry, et al. "Neurologic Injury in Isolated Sulfite Oxidase Deficiency." Canadian Journal of Neurological Sciences / Journal Canadien des Sciences Neurologiques 41, no. 1 (January 2014): 42–48. http://dx.doi.org/10.1017/s0317167100016243.

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Background:We review clinical, neuroimaging, and genetic information on six individuals with isolated sulfite oxidase deficiency (ISOD).Methods:All patients were examined, and clinical records, biochemistry, neuroimaging, and sulfite oxidase gene (SUOX) sequencing were reviewed.Results:Data was available on six individuals from four nuclear families affected by ISOD. Each individual began to seize within the first week of life. neurologic development was arrested at brainstem reflexes, and severe microcephaly developed rapidly. neuroimaging within days of birth revealed hypoplasia of the cerebellum and corpus callosum and damage to the supratentorial brain looking like severe hypoxic-ischemic injury that evolved into cystic hemispheric white matter changes. Affected individuals all had elevated urinary S-sulfocysteine and normal urinary xanthine and hypoxanthine levels diagnostic of ISOD. Genetic studies confirmed SUOX mutations in four patients.Conclusions:ISOD impairs systemic sulfite metabolism, and yet this genetic disease affects only the brain with damage that is commonly confused with the clinical and radiologic features of severe hypoxic-ischemic encephalopathy.

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Yang, Ming-Ming, Wei Huang, and Dian-Ming Jiang. "Tetramethylpyrazine protects Schwann cells from ischemia-like injury and increases cell survival in cold ischemic rat nerves." Brazilian Journal of Pharmaceutical Sciences 51, no. 1 (March 2015): 127–41. http://dx.doi.org/10.1590/s1984-82502015000100014.

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Tetramethylpyrazine (TMP), a major active ingredient of Ligusticum wallichi Franchat extract (a Chinese herb), exhibits neuroprotective properties in ischemia. In this study, we assessed its protective effects on Schwann cells (SCs) by culturing them in the presence of oxygen glucose deprivation (OGD) conditions and measuring cell survival in cold ischemic rat nerves. In the OGD-induced ischemic injury model of SCs, we demonstrated that TMP treatment not only reduced OGD-induced cell viability losses, cell death, and apoptosis of SCs in a dose-dependent manner, and inhibited LDH release, but also suppressed OGD-induced downregulation of Bcl-2 and upregulation of Bax and caspase-3, as well as inhibited the consequent activation of caspase-3. In the cold ischemic nerve model, we found that prolonged cold ischemic exposure for four weeks was markedly associated with the absence of SCs, a decrease in cell viability, and apoptosis in preserved nerve segments incubated in University of Wisconsin solution (UWS) alone. However, TMP attenuated nerve segment damage by preserving SCs and antagonizing the decrease in nerve fiber viability and increase in TUNEL-positive cells in a dose-dependent manner. Collectively, our results indicate that TMP not only provides protective effects in an ischemia-like injury model of cultured rat SCs by regulating Bcl-2, Bax, and caspase-3, but also increases cell survival and suppresses apoptosis in the cold ischemic nerve model after prolonged ischemic exposure for four weeks. Therefore, TMP may be a novel and effective therapeutic strategy for preventing peripheral nervous system ischemic diseases and improving peripheral nerve storage.

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Li, Yi, Jieli Chen, Michael Chopp, Lei Wang, and Weihang Zhao. "Cellular metabolic alterations after focal cerebral ischemia with or without bone marrow transplantation determined by cytochrome oxidase histochemistry." Stroke 32, suppl_1 (January 2001): 379. http://dx.doi.org/10.1161/str.32.suppl_1.379-c.

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P220 To determine the degree and extent of changes in cellular metabolic demand after stroke and bone marrow cell transplantation, a histochemistry assay of cytochrome oxidase (COx) which correlates with neuronal activity was employed,. Adult Wistar rats (n=9) were subjected to transient (2 h) middle cerebral artery occlusion (MCAo). At 1 d after ischemia, bone marrow stromal cells (MSCs, 4x10 5 in 10 :l) were transplanted intracerebrally into the ischemic boundary zone in the striatum and the cortex. The ischemia rats with (n=4) or without (n=5) MSC transplantation were sacrificed at 14 d after MCAo. Bone marrow cells were harvested from normal donor adult rats and cultured in Iscove s Modified Dulbecco s medium supplemented with 10% fetal bovine serum. MSCs were isolated by their adherence to the plastic dishes from the whole bone marrow cells at 72 h of incubation. Subsequently, the MSCs were cultured for 2 weeks and bromodeoxyuridine (BrdU, as a tracer to identify cells derived from bone marrow) was added into the medium at 3 d before transplantation. Cellular metabolic activity in the ischemic damaged brain was measured on a standard section per animal using quantitative histochemistry of COx with the Global Lab Image Analysis system. Immunohistochemistry staining was employed to identify BrdU-MSCs. COx was absent in the ischemic core in all experimental animals. However, COx activity was intense and prominent in the areas of BrdU-MSCs, as well as the subventricular zone (SVZ) of the adult forebrain. COx (72.8% of the normal hemisphere) was significantly increased (p=0.004) in the ipsilateral hemisphere after MCAo with MSC transplantation, compared with MCAo alone (30.4%). Since MSCs contain a population of marrow stem-like cells and the SVZ of the adult forebrain contains a population of neural stem-like cells, our data indicate that COx provides cellular metabolic evidence that stem-like cells (MSCs and SVZ cells) are activated in response to ischemic brain damage.

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Correa, Fernando, Maxime Gauberti, Jérôme Parcq, Richard Macrez, Yannick Hommet, Pauline Obiang, Miriam Hernangómez, et al. "Tissue plasminogen activator prevents white matter damage following stroke." Journal of Experimental Medicine 208, no. 6 (May 16, 2011): 1229–42. http://dx.doi.org/10.1084/jem.20101880.

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Tissue plasminogen activator (tPA) is the only available treatment for acute stroke. In addition to its vascular fibrinolytic action, tPA exerts various effects within the brain, ranging from synaptic plasticity to control of cell fate. To date, the influence of tPA in the ischemic brain has only been investigated on neuronal, microglial, and endothelial fate. We addressed the mechanism of action of tPA on oligodendrocyte (OL) survival and on the extent of white matter lesions in stroke. We also investigated the impact of aging on these processes. We observed that, in parallel to reduced levels of tPA in OLs, white matter gets more susceptible to ischemia in old mice. Interestingly, tPA protects murine and human OLs from apoptosis through an unexpected cytokine-like effect by the virtue of its epidermal growth factor–like domain. When injected into aged animals, tPA, although toxic to the gray matter, rescues white matter from ischemia independently of its proteolytic activity. These studies reveal a novel mechanism of action of tPA and unveil OL as a target cell for cytokine effects of tPA in brain diseases. They show overall that tPA protects white matter from stroke-induced lesions, an effect which may contribute to the global benefit of tPA-based stroke treatment.

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31

Chen, Wei, Wusong Tong, Yijun Guo, Bin He, Lei Chen, Wenjin Yang, Chenxing Wu, Dabin Ren, Ping Zheng, and Jiugeng Feng. "Upregulation of Connexin-43 is Critical for Irradiation-induced Neuroinflammation." CNS & Neurological Disorders - Drug Targets 17, no. 7 (August 29, 2018): 539–46. http://dx.doi.org/10.2174/1871527317666180706124602.

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Background: Radiation therapy is widely used for the treatment of pituitary adenomas. Unfortunately, it might raise the risk of ischemic stroke, with neuroinflammation being a major pathological process. Astrocytes are the most abundant cell type in the central nervous system and have been reported for playing important roles in ischemic stroke. Objective: Here we studied how γ-radiation would introduce astrocytes into a detrimental state for neuroinflammation and provide new theory evidence and target for the clinical management of inflammation- related neural damage after radiation-induced ischemic stroke. Method: HA-1800 cells were treated with γ-radiation and then the protein and mRNA levels of Connexin (Cx)-43 were evaluated by western and q-PCR. The culture supernatant was collected and the concentrations of the inflammatory factors were determined by ELISA. MiRNA complementary to Cx-43 was designed through the online tools. Results: Cx-43 is upregulated in the treatment of γ-radiation in astrocytes and γ-radiation introduced the detrimental function of astrocytes: cell viability was reduced while the apoptotic cells were increased. Inflammatory factors like tumor necrosis factor alpha, interferon gamma, interleukin-6, interleukin 1-beta were dramatically up-regulated by the irradiation. MiR-374a rescued irradiation induced Cx-43 up-regulation of astrocytes and eliminated detrimental function triggered by γ-radiation. Conclusion: Cx-43 expression level may play an important role in the inflammation-related neural damage after irradiation-induced ischemic stroke.

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Nakamura, Koutarou, Seiichiro Sakai, Jun Tsuyama, Akari Nakamura, Kento Otani, Kumiko Kurabayashi, Yoshiko Yogiashi, Hisao Masai, and Takashi Shichita. "Extracellular DJ-1 induces sterile inflammation in the ischemic brain." PLOS Biology 19, no. 5 (May 20, 2021): e3000939. http://dx.doi.org/10.1371/journal.pbio.3000939.

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Inflammation is implicated in the onset and progression of various diseases, including cerebral pathologies. Here, we report that DJ-1, which plays a role within cells as an antioxidant protein, functions as a damage-associated molecular pattern (DAMP) and triggers inflammation if released from dead cells into the extracellular space. We first found that recombinant DJ-1 protein induces the production of various inflammatory cytokines in bone marrow–derived macrophages (BMMs) and dendritic cells (BMDCs). We further identified a unique peptide sequence in the αG and αH helices of DJ-1 that activates Toll-like receptor 2 (TLR2) and TLR4. In the ischemic brain, DJ-1 is released into the extracellular space from necrotic neurons within 24 h after stroke onset and makes direct contact with TLR2 and TLR4 in infiltrating myeloid cells. Although DJ-1 deficiency in a murine model of middle cerebral artery occlusion did not attenuate neuronal injury, the inflammatory cytokine expression in infiltrating immune cells was significantly decreased. Next, we found that the administration of an antibody to neutralize extracellular DJ-1 suppressed cerebral post-ischemic inflammation and attenuated ischemic neuronal damage. Our results demonstrate a previously unknown function of DJ-1 as a DAMP and suggest that extracellular DJ-1 could be a therapeutic target to prevent inflammation in tissue injuries and neurodegenerative diseases.

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Martínez-Villota, Viviana Alexandra, Paulo Francisco Mera-Martínez, and José Darío Portillo-Miño. "Massive acute ischemic stroke after Bothrops spp. envenomation in southwestern Colombia: Case report and literature review." Biomédica 42, no. 1 (March 1, 2022): 9–17. http://dx.doi.org/10.7705/biomedica.6114.

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Bothrops spp. envenomation and its relationship with ischemic stroke has complex pathogenesis. Local effects such as edema, pain, redness, necrosis, and systemic manifestations like coagulation disorders, thrombosis, renal failure, and hemorrhage have been reported. Hemorrhagic stroke is a common neurological complication but ischemic stroke is poorly understood.We present here the case of a 50-year-old male with no comorbidities referred from a rural area in southwest Colombia with a Bothrops spp. snakebite on the left hand. On admission, the patient presented with a deterioration of consciousness and required mechanical ventilation assistance. The MRI showed multiple ischemic areas in the bilateral frontaltemporal and occipital regions. Two months later, the patient had a favorable resolution, although central paresis in the III and VI cranial nerves and positive Babinski’s sign persisted.As already mentioned, the pathophysiology of ischemic stroke due to snakebite is complex but the procoagulant activity of the venom components, the hypovolemic shock, the endothelial damage, and the thromboinflammation can explain it, and although it rarely occurs, it should be considered as a complication of ophidian accidents caused by Bothrops spp.

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Stephenson, Diane T., Karen Rash, and James A. Clemens. "Increase in Insulin-like Growth Factor II Receptor within Ischemic Neurons following Focal Cerebral Infarction." Journal of Cerebral Blood Flow & Metabolism 15, no. 6 (November 1995): 1022–31. http://dx.doi.org/10.1038/jcbfm.1995.128.

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The mechanisms underlying the response of the brain to ischemia are not fully understood. Biochemical and morphological changes following neocortical infarction can be investigated in rats using a model of focal cerebral ischemia induced by unilateral occlusion of the middle cerebral artery (MCA). Evaluation of ischemic damage often employs conventional histologic stains. Immunocytochemistry can be used as a valuable tool in this model to define changes in specific proteins of interest. In this study, an antiserum raised against insulin-like growth factor II (IGF-II) receptor was used to evaluate changes of IGF-II receptor immunoreactivity in the cerebral cortex of rats 4 and 7 days following permanent MCA occlusion. IGF-II receptor immunoreactivity was found to be associated with neocortical pyramidal neurons within the core of the ischemic infarct itself. The staining intensity was markedly elevated above that observed in nonischemic neurons. Immunopositive neurons exhibited a punctate staining pattern. These neurons appeared to correspond to argentophilic neurons, as defined by modified Bielschowsky silver staining. Evaluation of other neuronal markers revealed the absense of immunoreactivity for neuron-specific enolase and for tyrosine hydroxylase within the ischemic area. These observations show an increase in a specific growth factor receptor within neurons in the ischemic core of a focal infarct several days following permanent focal infarction, a time when neurons are presumed to be dead. The significance and the potential role of IGF-II receptor in lesion-induced plasticity are discussed.

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35

FERNÁNDEZ, MARTA, ALBERTO MEDINA, FERNANDO SANTOS, EDUARDO CARBAJO, JULIÁN RODRÍGUEZ, JESÚS ÁLVAREZ, and ANGELES COBO. "Exacerbated Inflammatory Response Induced by Insulin-Like Growth Factor I Treatment in Rats with Ischemic Acute Renal Failure." Journal of the American Society of Nephrology 12, no. 9 (September 2001): 1900–1907. http://dx.doi.org/10.1681/asn.v1291900.

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Abstract. In agreement with recent studies showing a deleterious effect of growth hormone treatment in critically ill patients, preliminary data showed that insulin-like growth factor I (IGF-I) administration increased the mortality rate of rats with ischemic acute renal failure (ARF). The present study was designed to investigate the mechanism responsible for this unexpected effect. Male rats with ischemic ARF were given subcutaneous IGF-I, 50 μg/100 g at 0, 8, and 16 h after reperfusion (ARF+IGF-I, n = 5) or were untreated (ARF, n = 5). A group of 5 sham-operated rats were used as controls. Rats were killed 48 h after declamping, and the following studies were performed: in serum, creatinine and urea nitrogen; and in kidneys, histologic damage score, cellular proliferation by bromodeoxyuridine labeling, apoptosis by morphologic criteria, macrophage infiltration by immunohistochemistry using a specific antibody against ED-1, neutrophil infiltration by naphthol AS-D chloroacetate esterase staining, and levels of IGF-I and IGF-I receptor mRNA by RNase protection assay. ARF and ARF+IGF-I groups had a severe and similar degree of renal failure. Kidney damage was histologically more evident in ARF+IGF-I (1.9 ± 0.1) than in ARF (1.3 ± 0.2) rats, and the number of neutrophils/mm2 of tissue was significantly greater in ARF+IGF-I than in ARF rats at the corticomedullary junction (52.3 ± 5.2 versus 37.2 ± 4.1) as well as at the renal medulla (172.5 ± 30.0 versus 42.1 ± 9.6). No other differences between the groups were found. It is concluded that IGF-I treatment enhanced the inflammatory response in rats with ischemic ARF. Cell toxicity derived from increased neutrophil accumulation might play a key role in the greater mortality risk of critically ill patients that are treated with growth hormone.

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Feng, Yan, and Wei Chao. "Toll-Like Receptors and Myocardial Inflammation." International Journal of Inflammation 2011 (2011): 1–21. http://dx.doi.org/10.4061/2011/170352.

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Toll-like receptors (TLRs) are a member of the innate immune system. TLRs detect invading pathogens through the pathogen-associated molecular patterns (PAMPs) recognition and play an essential role in the host defense. TLRs can also sense a large number of endogenous molecules with the damage-associated molecular patterns (DAMPs) that are produced under various injurious conditions. Animal studies of the last decade have demonstrated that TLR signaling contributes to the pathogenesis of the critical cardiac conditions, where myocardial inflammation plays a prominent role, such as ischemic myocardial injury, myocarditis, and septic cardiomyopathy. This paper reviews the animal data on (1) TLRs, TLR ligands, and the signal transduction system and (2) the important role of TLR signaling in these critical cardiac conditions.

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Desposito, Dorinne, Ludovic Waeckel, Louis Potier, Christine Richer, Ronan Roussel, Nadine Bouby, and Francois Alhenc-Gelas. "Kallikrein(K1)-kinin-kininase (ACE) and end-organ damage in ischemia and diabetes: therapeutic implications." Biological Chemistry 397, no. 12 (December 1, 2016): 1217–22. http://dx.doi.org/10.1515/hsz-2016-0228.

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Abstract Genetic and pharmacological studies, clinical and experimental, focused on kallikrein-K1, kinin receptors and ACE/kininase II suggest that kinin release in the settings of ischemia or diabetes reduces organ damage, especially in the heart and kidney. Kinin bioavailability may be a limiting factor for efficacy of current kinin-potentiating drugs, like ACE inhibitors. Primary activation of kinin receptors by prototypic pharmacological agonists, peptidase-resistant, selective B1 or B2, displays therapeutic efficacy in experimental cardiac and peripheral ischemic and diabetic diseases. B1R agonism was especially efficient in diabetic animals and had no unwanted effects. Clinical development of kinin receptor agonists may be warranted.

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Davies, Christine A., Sarah A. Loddick, Sylvie Toulmond, R. Paul Stroemer, Joanne Hunt та Nancy J. Rothwell. "The Progression and Topographic Distribution of Interleukin-1β Expression after Permanent Middle Cerebral Artery Occlusion in the Rat". Journal of Cerebral Blood Flow & Metabolism 19, № 1 (січень 1999): 87–98. http://dx.doi.org/10.1097/00004647-199901000-00010.

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The cytokine interleukin-1 (IL-1) has been implicated in the exacerbation of ischemic damage in the brains of rodents. This study has ascertained the cellular localization and chronologic and topographic distribution of pro/mature interleukin-1β (IL-1β) protein 0.5, 1, 2, 6, 24, and 48 hours after ischemia by subjecting rats to permanent unilateral occlusion of the middle cerebral artery. Interleukin-1β was localized immunocytochemically in vibratome sections of perfusion-fixed brains. The cells that expressed IL-1β had the morphologic features of microglia and macrophages. Interleukin-1β was first detected 1 hour after occlusion in ipsilateral meningeal macrophage-like cells. By 6 hours, pro/mature IL-1β-immunoreactive (IL-1βir) putative microglia were present in the ischemic cerebral cortex, corpus callosum, caudoputamen, and surrounding tissue. By 24 and 48 hours after ischemia, the number and spread of IL-1βir cells increased greatly, including those resembling activated microglia and macrophages, as the core of the infarct became infiltrated. Interleukin-1βir cells also were present in apparently undamaged tissue, adjacent to the lesion ipsilaterally, and contralaterally in the cerebral cortex, dorsal corpus callosum, dorsal caudoputamen, and hippocampus. These results support the functional role of IL-1 in ischemic brain damage and reveal a distinct temporal and spatial expression of IL-1β protein in cells believed to be microglia and macrophages.

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Tsung, Allan, John R. Klune, Xianghong Zhang, Geetha Jeyabalan, Zongxian Cao, Ximei Peng, Donna B. Stolz, David A. Geller, Matthew R. Rosengart, and Timothy R. Billiar. "HMGB1 release induced by liver ischemia involves Toll-like receptor 4–dependent reactive oxygen species production and calcium-mediated signaling." Journal of Experimental Medicine 204, no. 12 (November 5, 2007): 2913–23. http://dx.doi.org/10.1084/jem.20070247.

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Ischemic tissues require mechanisms to alert the immune system of impending cell damage. The nuclear protein high-mobility group box 1 (HMGB1) can activate inflammatory pathways when released from ischemic cells. We elucidate the mechanism by which HMGB1, one of the key alarm molecules released during liver ischemia/reperfusion (I/R), is mobilized in response to hypoxia. HMGB1 release from cultured hepatocytes was found to be an active process regulated by reactive oxygen species (ROS). Optimal production of ROS and subsequent HMGB1 release by hypoxic hepatocytes required intact Toll-like receptor (TLR) 4 signaling. To elucidate the downstream signaling pathways involved in hypoxia-induced HMGB1 release from hepatocytes, we examined the role of calcium signaling in this process. HMGB1 release induced by oxidative stress was markedly reduced by inhibition of calcium/calmodulin-dependent kinases (CaMKs), a family of proteins involved in a wide range of calcium-linked signaling events. In addition, CaMK inhibition substantially decreased liver damage after I/R and resulted in accumulation of HMGB1 in the cytoplasm of hepatocytes. Collectively, these results demonstrate that hypoxia-induced HMGB1 release by hepatocytes is an active, regulated process that occurs through a mechanism promoted by TLR4-dependent ROS production and downstream CaMK-mediated signaling.

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Sameshima, Hiroshi, and Tsuyomu Ikenoue. "Hypoxic-Ischemic Neonatal Encephalopathy: Animal Experiments for Neuroprotective Therapies." Stroke Research and Treatment 2013 (2013): 1–11. http://dx.doi.org/10.1155/2013/659374.

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Hypoxic-ischemic neonatal encephalopathy and ensuing brain damage is still an important problem in modern perinatal medicine. In this paper, we would like to share some of the results of our recent studies on neuroprotective therapies in animal experiments, as well as some literature reviews. From the basic animal studies, we have now obtained some possible candidates for therapeutic measures against hypoxic-ischemic neonatal encephalopathy. For example, they are hypothermia, rehabilitation, free radical scavenger, neurotrophic factors and growth factors, steroid, calcium channel blocker, vagal stimulation, some anti apoptotic agents, pre- and post conditioning, antioxidants, cell therapy with stem cells, modulators of K(+)-ATP channels, and so on. Whether combination of these therapies may be more beneficial than any single therapy needs to be clarified. Hypoxia-ischemia is a complicated condition, in which the cause, severity, and time-course are different in each case. Likewise, each fetus has its own inherent potentials such as adaptation, preconditioning-tolerance, and intolerance. Therefore, further extensive studies are required to establish an individualized strategy for neuroprotection against perinatal hypoxic-ischemic insult.

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Yao, Hui-Wen, and Chia-Yi Kuan. "Early neutrophil depletion reduces inflammation-sensitized hypoxic-ischemic brain injury in mouse neonates." Journal of Immunology 200, no. 1_Supplement (May 1, 2018): 102.10. http://dx.doi.org/10.4049/jimmunol.200.supp.102.10.

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Abstract Hypoxia-ischemia to brain triggers immune responses consisting of activation and recruitment of leukocytes and expression of pro-inflammatory mediators. Inducing neutropenia confers protection against cerebral ischemia in adult and neonatal rats, but it remains unclear if neutrophils enhances neonatal brain damage in inflammation (LPS)-sensitized hypoxic-ischemic (HI) insults to mice. Herein, we demonstrated that following LPS/HI insult, the mRNA expression of C-X-C motif ligands 1 and 2, two potent neutrophil chemoattractants, granulocyte colony-stimulating factor that stimulates the bone marrow to produce and release granulocytes, and pro-inflammatory cytokines, including interleukins 1β and 6 and tumor necrosis factor α, were increased in mouse brains. As early as six hours after insult, neutrophil infiltration was readily detectable in mouse brains and increased with time, especially in those brains with severe damage. Neutrophils either resided within vessel like structures or accumulated within brain parenchyma. In addition, infiltrated neutrophils expressed interleukin 1β and tumor necrosis factor α, as well as citrullinated histones, a marker of neutrophil extracellular traps, in the damaged brains. Importantly, prophylactic depletion of neutrophils from the periphery reduced leukocyte infiltration, the expression of pro-inflammatory mediators in mouse brains, and brain atrophy, whereas post-insult depletion of neutrophils conferred marginal protection. Collectively, our data support the pathogenic roles of neutrophils in the acute phase of inflammation-sensitized hypoxia-ischemia brain injury.

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Ma, Yi, Suresh L. Mehta, Baisong Lu, and P. Andy Li. "Deficiency in the inner mitochondrial membrane peptidase 2-like (Immp21) gene increases ischemic brain damage and impairs mitochondrial function." Neurobiology of Disease 44, no. 3 (December 2011): 270–76. http://dx.doi.org/10.1016/j.nbd.2011.06.019.

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Tomimatsu, Takuji, Hirotsugu Fukuda, Takeshi Kanagawa, Junwu Mu, Toru Kanzaki, and Yuji Murata. "Effects of hyperthermia on hypoxic-ischemic brain damage in the immature rat: Its influence on caspase-3-like protease." American Journal of Obstetrics and Gynecology 188, no. 3 (March 2003): 768–73. http://dx.doi.org/10.1067/mob.2003.163.

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44

Detillieux, Karen A., Peter A. Cattini, and Elissavet Kardami. "Beyond angiogenesis: the cardioprotective potential of fibroblast growth factor-2." Canadian Journal of Physiology and Pharmacology 82, no. 12 (December 1, 2004): 1044–52. http://dx.doi.org/10.1139/y04-126.

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In the field of cardiovascular research, a number of independent approaches have been explored to protect the heart from acute and chronic ischemic damage. Fibroblast growth factor-2 (FGF-2) recently has received considerable attention with respect to its angiogenic potential. While therapeutic angiogenesis may serve to salvage chronically ischemic myocardium, more acute treatments are in demand to increase cardiac resistance to injury (preconditioning) and to guard against secondary injury after an acute ischemic insult. Here, we look beyond the angiogenic potential of FGF-2 and examine its acute cardioprotective activity as demonstrated under experimental conditions, both as an agent of a preconditioning-like response and for secondary injury prevention at the time of reperfusion. Factors to consider in moving to the clinical setting will be discussed, including issues of dosage, treatment duration, and routes of administration. Finally, issues of safety and clinical trial design will be considered. The prospect of such a multipotent growth factor having clinical usefulness opens the door to effective treatment of both acute and chronic ischemic heart disease, something well worth the attention of the cardiovascular community.Key words: fibroblast growth factor-2, ischemia, reperfusion injury, cardioprotection, angiogenesis, apoptosis.

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45

Yang, Jun, Xin Guo, Jian Yang, Jia-wang Ding, Song Li, Rui Yang, Zhi-xing Fan, and Chao-jun Yang. "RP105 Protects Against Apoptosis in Ischemia/Reperfusion-Induced Myocardial Damage in Rats by Suppressing TLR4-Mediated Signaling Pathways." Cellular Physiology and Biochemistry 36, no. 6 (2015): 2137–48. http://dx.doi.org/10.1159/000430180.

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Background: Myocardial apoptosis is heavily implicated in the myocardial damage caused by ischemia-reperfusion (I/R). Toll-like receptor 4 (TLR4) is a potent inducer of these apoptotic cascades. In contrast, the radioprotective 105 kDa protein (RP105) is a specific negative regulator of TLR4 signaling pathways. However, the precise mechanisms by which RP105 inhibits myocardium apoptosis via TLR4-associated pathways during I/R is not fully understood. Methods: We utilized a rat model of myocardial ischemic reperfusion injury (MIRI). Animals were pre-treated with Ad-EGFP adenovirus, Ad-EGFP-RP105 adenovirus, saline, or nothing (sham). After three days, rats underwent a 30min left anterior descending coronary artery occlusion and a 4h reperfusion. Mycardial tissue was assessed by immunohistochemistry, TUNEL-staining, Western blot, quantitative RT-PCR, and a morphometric assay. Results: RP105 overexpression resulted in a reduction in infarct size, fewer TUNEL-positive cardiomyocytes, and a reduction in mitochondrial-associated apoptosis cascade activity. Further, RP105 overexpression repressed I/R-induced myocardial injury by attenuating myocardial apoptosis. This was mediated by inhibiting TLR4 activation and the phosphorylation of P38MAPK and the downstream transcription factor AP-1. Conclusion: RP105 overexpression leads to the de-activation of TLR4, P38MAPK, and AP-1 signaling pathways, and subsequently represses apoptotic cascades and ensuing damage of myocardial ischemic reperfusion. These findings may become the basis of a novel therapeutic approach for reducing of cardiac damage caused by MIRI.

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46

Nanetti, L., A. Vignini, F. Raffaelli, R. Taffi, M. Silvestrini, L. Provinciali, and L. Mazzanti. "Sialic Acid and Sialidase Activity in Acute Stroke." Disease Markers 25, no. 3 (2008): 167–73. http://dx.doi.org/10.1155/2008/613272.

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Stroke is a heterogeneous syndrome caused by multiple disease mechanisms, resulting in a disruption of cerebral blood flow with subsequent tissue damage. It is well known that erythrocytes have a large amount of sialic acid and could represent a model to investigate changes occurring in a pathology like stroke. The aim of this study was to investigate a possible relationship among erythrocyte membrane, plasma and sialic acid content. The possible impact of the sialic acid content and the activity of sialidase on stroke severity was also evaluated.The study population consisted of 54 patients with a first stroke and of 53 age-and sex matched healthy volunteers.The total bound sialic acid was substantially decreased in patients. There was a significant correlation between the sialidase activity values and the severity of the neurological deficit defined by the National Institute of Health Stroke Scale.This study shows that low sialic acid erythrocyte concentrations with contemporary high sialic acid plasma levels and elevated sialidase activity can be considered as markers of ischemic stroke. Further investigations are needed to clarify the possible role of these biochemical changes in producing and sustaining cerebral ischemic damage.

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47

Anttila, Jenni E., Suvi Pöyhönen, and Mikko Airavaara. "Secondary Pathology of the Thalamus after Focal Cortical Stroke in Rats is not Associated with Thermal or Mechanical Hypersensitivity and is Not Alleviated by Intra-Thalamic Post-Stroke Delivery of Recombinant CDNF or MANF." Cell Transplantation 28, no. 4 (April 2019): 425–38. http://dx.doi.org/10.1177/0963689719837915.

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A stroke affecting the somatosensory pathway can trigger central post-stroke pain syndrome (CPSP). The symptoms often include hyperalgesia, which has also been described in rodents after the direct damage of the thalamus. Previous studies have shown that hemorrhagic stroke or ischemia caused by vasoconstriction in the thalamus induces increased pain sensitivity. We investigated whether inducing secondary damage in the thalamus by a cortical stroke causes similar pain hypersensitivity as has previously been reported with direct ischemic injury. We induced a focal cortical ischemia-reperfusion injury in male rats, quantified the amount of secondary neurodegeneration in the thalamus, and measured whether the thalamic neurodegeneration is associated with thermal or mechanical hypersensitivity. After one month, we observed extensive neuronal degeneration and found approximately 40% decrease in the number of NeuN+ cells in the ipsilateral thalamus. At the same time, there was a massive accumulation—a 30-fold increase—of phagocytic cells in the ipsilateral thalamus. However, despite the evident damage in the thalamus, we did not observe thermal or mechanical sensitization. Thus, thalamic neurodegeneration after cortical ischemia-reperfusion does not induce CPSP-like symptoms in rats, and these results suggest that direct ischemic damage is needed for CPSP induction. Despite not observing hyperalgesia, we investigated whether administration of cerebral dopamine neurotrophic factor (CDNF) and mesencephalic astrocyte-derived neurotrophic factor (MANF) into the ipsilateral thalamus would reduce the secondary damage. We gave a single injection (10 µg) of recombinant CDNF or MANF protein into the thalamus at 7 days post-stroke. Both CDNF and MANF treatment promoted the functional recovery but had no effect on the neuronal loss or the amount of phagocytic cells in the thalamus.

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Kayumova, G. H., and V. A. Razin. "Age- and gender-related features of indicators of protein growth factors and damage in acute coronary syndrome." Kazan medical journal 97, no. 4 (August 15, 2016): 507–13. http://dx.doi.org/10.17750/kmj2015-507.

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Aim. To analyze the pregnancy associated protein A and insulin-like growth factor 1 levels in blood plasma of patients with acute coronary syndrome and determination of gender- and age-related features of proteins values.Methods. The study included 71 patients with acute coronary syndrome, including 47 men and 24 women. The control group consisted of 20 healthy people matched for age and sex, the comparison group - 40 patients with a diagnosis of «hypertension» and «chronic ischemic heart disease». Pregnancy-associated plasma protein A, and insulin-like growth factor 1 determination was performed.Results. The concentration of a pregnancy-associated plasma protein A was higher in acute coronary syndrome compared with control and comparison groups. The content of insulin-like growth factor-1 in myocardial infarction is lower than in the comparison group. An increase in concentration of insulin-like growth factor 1 in unstable angina has no significant differences from the control and comparison groups. The highest levels of insulin-like growth factor-1 are registered in the comparison group, the lowest ones - in the subgroup with a fatal outcome. A statistically significant difference between the parameters in men and women was demonstrated in the groups with acute coronary syndrome and unstable angina for insulin-like growth factor 1, in the group with myocardial infarction - for a pregnancy-associated plasma protein A. Insulin-like growth factor 1 levels inversely correlated with age, which confirms reparative role of the protein.Conclusion. Pregnancy-associated plasma protein A and insulin-like growth factor 1 are new highly sensitive biochemical markers of vascular inflammation and injury, their levels can be used to predict the instability of atherosclerotic plaque in acute coronary pathology and assessing the disease prognosis.

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Lobenwein, Daniela, Rosalie Huber, Lars Kerbler, Alexandra Gratl, Sabine Wipper, Can Gollmann-Tepeköylü, and Johannes Holfeld. "Neuronal Pre- and Postconditioning via Toll-like Receptor 3 Agonist or Extracorporeal Shock Wave Therapy as New Treatment Strategies for Spinal Cord Ischemia: An In Vitro Study." Journal of Clinical Medicine 11, no. 8 (April 11, 2022): 2115. http://dx.doi.org/10.3390/jcm11082115.

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Spinal cord ischemia (SCI) is a devastating and unpredictable complication of thoracoabdominal aortic repair. Postischemic Toll-like receptor 3 (TLR3) activation through either direct agonists or shock wave therapy (SWT) has been previously shown to ameliorate damage in SCI models. Whether the same applies for pre- or postconditioning remains unclear. In a model of cultured SHSY-5Y cells, preconditioning with either poly(I:C), a TLR3 agonist, or SWT was performed before induction of hypoxia, whereas postconditioning treatment was performed after termination of hypoxia. We measured cytokine expression via RT-PCR and utilized Western blot analysis for the analysis of signaling and apoptosis. TLR3 activation via poly(I:C) significantly reduced apoptotic markers in both pre- and postconditioning, the former yielding more favorable results through an additional suppression of TLR4 and its downstream signaling. On the contrary, SWT showed slightly more favorable effects in the setting of postconditioning with significantly reduced markers of apoptosis. Pre- and post-ischemic direct TLR3 activation as well as post-ischemic SWT can decrease apoptosis and proinflammatory cytokine expression significantly in vitro and might therefore pose possible new treatment strategies for ischemic spinal cord injury.

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Douglas, Heather A., Jennifer K. Callaway, Jeremy Sword, Sergei A. Kirov, and R. David Andrew. "Potent inhibition of anoxic depolarization by the sodium channel blocker dibucaine." Journal of Neurophysiology 105, no. 4 (April 2011): 1482–94. http://dx.doi.org/10.1152/jn.00817.2010.

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Recurring waves of peri-infarct depolarizations (PIDs) propagate across gray matter in the hours and days following stroke, expanding the primary site of injury. Ischemic depolarization (termed anoxic depolarization or AD in live brain slices) is PID-like but immediately arises in the more metabolically compromised ischemic core. This causes dramatic neuronal and astrocyte swelling and dendritic beading with spine loss within minutes, resulting in acute cell death. AD is evoked in rodent neocortical slices by suppressing the Na+/K+-ATPase pump with either oxygen/glucose deprivation (OGD) or exposure to ouabain. The process driving AD and PIDs remains poorly understood. Here we show that dibucaine is a potent drug inhibiting AD because of its high binding affinity to the Na+ channel. Field recording reveals that, when superfused with ouabain (5 min), neocortical slices pretreated with 1 μM dibucaine for 45 min display either no AD or delayed AD onset compared with untreated controls. If ouabain exposure is extended to 10 min, 1 μM dibucaine is still able to delay AD onset by ∼60%. Likewise, it delays OGD-evoked AD onset by ∼54% but does not depress action potentials (APs) or evoked orthodromic field potentials. Increasing dibucaine to 10 μM inhibits AP firing, gradually putting the slice into a stasis that inhibits AD onset but also renders the slice functionally quiescent. Two-photon microscopy reveals that 10 μM dibucaine pretreatment prevents or helps reverse ouabain-induced structural neuronal damage. Although the therapeutic range of dibucaine is quite narrow, dibucaine-like drugs could prove therapeutically useful in inhibiting PIDs and their resultant neuronal damage.

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