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Cecchini, Gloria, Alessandro Scaglione, Anna Letizia Allegra Mascaro, Curzio Checcucci, Emilia Conti, Ihusan Adam, Duccio Fanelli, Roberto Livi, Francesco Saverio Pavone, and Thomas Kreuz. "Cortical propagation tracks functional recovery after stroke." PLOS Computational Biology 17, no. 5 (May 17, 2021): e1008963. http://dx.doi.org/10.1371/journal.pcbi.1008963.
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Stroke is a debilitating condition affecting millions of people worldwide. The development of improved rehabilitation therapies rests on finding biomarkers suitable for tracking functional damage and recovery. To achieve this goal, we perform a spatiotemporal analysis of cortical activity obtained by wide-field calcium images in mice before and after stroke. We compare spontaneous recovery with three different post-stroke rehabilitation paradigms, motor training alone, pharmacological contralesional inactivation and both combined. We identify three novel indicators that are able to track how movement-evoked global activation patterns are impaired by stroke and evolve during rehabilitation: the duration, the smoothness, and the angle of individual propagation events. Results show that, compared to pre-stroke conditions, propagation of cortical activity in the subacute phase right after stroke is slowed down and more irregular. When comparing rehabilitation paradigms, we find that mice treated with both motor training and pharmacological intervention, the only group associated with generalized recovery, manifest new propagation patterns, that are even faster and smoother than before the stroke. In conclusion, our new spatiotemporal propagation indicators could represent promising biomarkers that are able to uncover neural correlates not only of motor deficits caused by stroke but also of functional recovery during rehabilitation. In turn, these insights could pave the way towards more targeted post-stroke therapies.
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Zaidi, Syed Kashif, Md Nasrul Hoda, Shams Tabrez, and Mohammad Imran Khan. "Pharmacological Inhibition of Class III Alcohol Dehydrogenase 5: Turning Remote Ischemic Conditioning Effective in a Diabetic Stroke Model." Antioxidants 11, no. 10 (October 18, 2022): 2051. http://dx.doi.org/10.3390/antiox11102051.
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The restoration of cerebral blood flow (CBF) to achieve brain tissue oxygenation (PbtO2) is the primary treatment for ischemic stroke, a significant cause of adult mortality and disability worldwide. Nitric oxide (NO) and its bioactive s-nitrosylated (SNO) reservoirs, such as s-nitrosoglutathione (GSNO), induce hypoxic vasodilation to enhance CBF during ischemia. The endogenous pool of SNOs/GSNO is enhanced via the activation of endothelial NO synthase (eNOS/NOS3) and by the suppression of class III alcohol dehydrogenase 5 (ADH5), also known as GSNO reductase (GSNOR). Remote ischemic conditioning (RIC), which augments NOS3 activity and SNO, is an emerging therapy in acute stroke. However, RIC has so far shown neutral effects in stroke clinical trials. As the majority of stroke patients are presented with endothelial dysfunctions and comorbidities, we tested the hypothesis that NOS3 dysfunction and diabetes will abolish the protective effects of RIC therapy in stroke, and the prior inhibition of GSNOR will turn RIC protective. Our data demonstrate that RIC during thrombotic stroke failed to enhance the CBF and the benefits of thrombolysis in NOS3 mutant (NOS3+/−) mice, a genetic model of NOS3 dysfunction. Interestingly, thrombotic stroke in diabetic mice enhanced the activity of GSNOR as early as 3 h post-stroke without decreasing the plasma nitrite (NO2−). In thrombotic stroke, neither a pharmacological inhibitor of GSNOR (GRI) nor RIC therapy alone was protective in diabetic mice. However, prior treatment with GRI followed by RIC enhanced the CBF and improved recovery. In a reperfused stroke model, the GRI–RIC combination therapy in diabetic mice augmented PbtO2, a translatory signature of successful microvascular reflow. In addition, RIC therapy unexpectedly increased the inflammatory markers at 6 h post-stroke in diabetic stroke that were downregulated in combination with GRI while improving the outcomes. Thus, we conclude that preexisting NOS3 dysfunctions due to comorbidities may neutralize the benefits of RIC in stroke, which can be turned protective in combination with GRI. Our findings may support the future clinical trial of RIC in comorbid stroke. Further studies are warranted to test and develop SNO reservoirs as the blood-associated biomarker to monitor the response and efficacy of RIC therapy in stroke.
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Zhao, Haiping, Guangwen Li, Sijia Zhang, Fangfang Li, Rongliang Wang, Zhen Tao, Qingfeng Ma, et al. "Inhibition of histone deacetylase 3 by MiR-494 alleviates neuronal loss and improves neurological recovery in experimental stroke." Journal of Cerebral Blood Flow & Metabolism 39, no. 12 (September 11, 2019): 2392–405. http://dx.doi.org/10.1177/0271678x19875201.
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HDAC3 is an essential negative regulator of neuronal plasticity and memory formation. Although a chemical inhibitor has been invented, little is known about its endogenous modulators. We explored whether miR-494 affects HDAC3-mediated neuronal injury following acute ischemic stroke. A substantial increase in plasma miR-494 was detected in AIS patients and was positively associated with the mRS at one year after symptom onset. The miR-494 levels were transiently increased in the infarcted brain tissue of mice. In contrast, miR-494 levels were reduced in neurons but increased in the medium after OGD. Intracerebroventricular injection of miR-494 agomir reduced neuronal apoptosis and infarct volume at the acute stage of MCAO, promoted axonal plasticity and long-term outcomes at the recovery stage, suppressed neuronal ataxin-3 and HDAC3 expression and increased acetyl-H3K9 levels in the ipsilateral hemisphere. In vitro studies confirmed that miR-494 posttranslationally inhibited HDAC3 in neurons and prevented OGD-induced neuronal axonal injury. The HDAC3 inhibitor increased acetyl-H3K9 levels and reversed miR-494 antagomir-aggravated acute cerebral ischemic injury, as well as brain atrophy and long-term functional recovery. These results suggest that miR-494 may serve as a predictive biomarker of functional outcomes in AIS patients and a potential therapeutic target for the treatment of ischemic stroke.
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Leon, Lisa R., David A. DuBose, and Clifford W. Mason. "Heat stress induces a biphasic thermoregulatory response in mice." American Journal of Physiology-Regulatory, Integrative and Comparative Physiology 288, no. 1 (January 2005): R197—R204. http://dx.doi.org/10.1152/ajpregu.00046.2004.
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Previous animal models of heat stress have been compromised by methodologies, such as restraint and anesthesia, that have confounded our understanding of the core temperature (Tc) responses elicited by heat stress. Using biotelemetry, we developed a heat stress model to examine Tcresponses in conscious, unrestrained C57BL/6J male mice. Before heat stress, mice were acclimated for >4 wk to an ambient temperature (Ta) of 25°C. Mice were exposed to Taof 39.5 ± 0.2°C, in the absence of food and water, until they reached maximum Tcof 42.4 ( n = 11), 42.7 ( n = 12), or 43.0°C ( n = 11), defined as mild, moderate, and extreme heat stress, respectively. Heat stress induced an ∼13% body weight loss that did not differ by final group Tc; however, survival rate was affected by final Tc(100% at 42.4°C, 92% at 42.7°C, and 46% at 43°C). Hypothermia (Tc< 34.5°C) developed after heat stress, with the depth and duration of hypothermia significantly enhanced in the moderate and extreme compared with the mild group. Regardless of heat stress severity, every mouse that transitioned out of hypothermia (survivors only) developed a virtually identical elevation in Tcthe next day, but not night, compared with nonheated controls. To test the effect of the recovery Ta, a group of mice ( n = 5) were acclimated for >4 wk and recovered at Taof 30°C after moderate heat stress. Recovery at 30°C resulted in 0% survival within ∼2 h after cessation of heat stress. Using biotelemetry to monitor Tcin the unrestrained mouse, we show that recovery from acute heat stress is associated with prolonged hypothermia followed by an elevation in daytime Tcthat is dependent on Ta. These thermoregulatory responses to heat stress are key biomarkers that may provide insight into heat stroke pathophysiology.
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Garcia, Christian K., Gerard P. Robinson, Bryce J. Gambino, Michael T. Rua, Orlando Laitano, and Thomas L. Clanton. "The impact of castration on physiological responses to exertional heat stroke in mice." PLOS ONE 17, no. 10 (October 13, 2022): e0275715. http://dx.doi.org/10.1371/journal.pone.0275715.
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Introduction The capability of male mice to exercise in hot environments without succumbing to exertional heat stroke (EHS) is markedly blunted compared to females. Epidemiological evidence in humans and other mammals also suggests some degree of greater vulnerability to heat stroke in males compared to females. The origins of these differences are unknown, but testosterone has previously been shown to induce faster elevations in core temperature during acute, passive heat exposure. In this study, we tested the hypothesis that loss of testosterone and related sex hormones through castration would improve the performance and heat tolerance of male mice during EHS exposure. Methods Twenty-four male mice were randomly divided into 3 groups, untreated EHS mice (SHAM-EHS), castrated EHS mice (CAS+EHS) and naïve exercise controls (NAIVE). Exercise performance and physiological responses in the heat were monitored during EHS and early recovery. Two weeks later, blood and tissues were collected and analyzed for biomarkers of cardiac damage and testosterone. Results Core temperature in CAS+EHS rose faster to 39.5°C in the early stages of the EHS trial (P<0.0001). However, both EHS groups ran similar distances, exhibited similar peak core temperatures and achieved similar exercise times in the heat, prior to symptom limitation (unconsciousness). CAS+EHS mice had ~10.5% lower body mass at the time of EHS, but this provided no apparent advantage in performance. There was no evidence of myocardial damage in any group, and testosterone levels were undetectable in CAS+EHS after gonadectomy. Conclusions The results of these experiments exclude the hypothesis that reduced performance of male mice during EHS trials is due to the effects of male sex hormones or intact gonads. However, the results are consistent with a role of male sex hormones or intact gonads in suppressing the early and rapid rise in core temperature during the early stages of exercise in the heat.
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Rodriguez-Grande, Beatriz, Matimba Swana, Loan Nguyen, Pavlos Englezou, Samaneh Maysami, Stuart M. Allan, Nancy J. Rothwell, Cecilia Garlanda, Adam Denes, and Emmanuel Pinteaux. "The Acute-Phase Protein PTX3 is an Essential Mediator of Glial Scar Formation and Resolution of Brain Edema after Ischemic Injury." Journal of Cerebral Blood Flow & Metabolism 34, no. 3 (December 18, 2013): 480–88. http://dx.doi.org/10.1038/jcbfm.2013.224.
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Acute-phase proteins (APPs) are key effectors of the immune response and are routinely used as biomarkers in cerebrovascular diseases, but their role during brain inflammation remains largely unknown. Elevated circulating levels of the acute-phase protein pentraxin-3 (PTX3) are associated with worse outcome in stroke patients. Here we show that PTX3 is expressed in neurons and glia in response to cerebral ischemia, and that the proinflammatory cytokine interleukin-1 (IL-1) is a key driver of PTX3 expression in the brain after experimental stroke. Gene deletion of PTX3 had no significant effects on acute ischemic brain injury. In contrast, the absence of PTX3 strongly compromised blood–brain barrier integrity and resolution of brain edema during recovery after ischemic injury. Compromised resolution of brain edema in PTX3-deficient mice was associated with impaired glial scar formation and alterations in scar-associated extracellular matrix production. Our results suggest that PTX3 expression induced by proinflammatory signals after ischemic brain injury is a critical effector of edema resolution and glial scar formation. This highlights the potential role for inflammatory molecules in brain recovery after injury and identifies APPs, in particular PTX3, as important targets in ischemic stroke and possibly other brain inflammatory disorders.
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Grosman, Benyamin, Osman S. Shaik, Bryan G. Helwig, Lisa R. Leon, and Francis J. Doyle. "A physiological systems approach to modeling and resetting of mouse thermoregulation under heat stress." Journal of Applied Physiology 111, no. 3 (September 2011): 938–45. http://dx.doi.org/10.1152/japplphysiol.00519.2010.
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Heat stroke (HS) is a serious civilian and military health issue. Due to the limited amount of experimental data available in humans, this study was conducted on a mouse mathematical model fitted on experimental data collected from mice under HS conditions, with the assumption there is good agreement among mammals. Core temperature (Tc) recovery responses in a mouse model consist of hypothermia and delayed fever during 24 h of recovery that represent potential biomarkers of HS severity. The objective of this study was to develop a simulation model of mouse Tc responses and identify optimal treatment windows for HS recovery using a three-dimensional predictive heat transfer simulation model. Several bioenergetic simulation variables, including nonlinear metabolic heat production (W/m3), temperature-dependent convective heat transfer through blood mass perfusion (W/m3), and activity-related changes in circadian Tc were used for model simulation. The simulation results predicted the experimental data with few disparities. Using this simulation model, we tested a series of ambient temperature treatment strategies to minimize hypothermia and delayed fever to accelerate HS recovery. Using a genetic algorithm, we identified eight time segments (ambient temperature = 27, 30, 31, 29, 28, 28, 27, 26°C) of 110 min total duration that optimized HS recovery in our model simulation.
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Vaibhav, Kumar, Molly Braun, Mohammad Badruzzaman Khan, Sumbul Fatima, Nancy Saad, Adarsh Shankar, Zenab T. Khan, et al. "Remote ischemic post-conditioning promotes hematoma resolution via AMPK-dependent immune regulation." Journal of Experimental Medicine 215, no. 10 (September 6, 2018): 2636–54. http://dx.doi.org/10.1084/jem.20171905.
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Spontaneous intracerebral hemorrhage (ICH) produces the highest acute mortality and worst outcomes of all stroke subtypes. Hematoma volume is an independent determinant of ICH patient outcomes, making clot resolution a primary goal of clinical management. Herein, remote-limb ischemic post-conditioning (RIC), the repetitive inflation–deflation of a blood pressure cuff on a limb, accelerated hematoma resolution and improved neurological outcomes after ICH in mice. Parabiosis studies revealed RIC accelerated clot resolution via a humoral-mediated mechanism. Whereas RIC increased anti-inflammatory macrophage activation, myeloid cell depletion eliminated the beneficial effects of RIC after ICH. Myeloid-specific inactivation of the metabolic regulator, AMPKα1, attenuated RIC-induced anti-inflammatory macrophage polarization and delayed hematoma resolution, providing a molecular link between RIC and immune activation. Finally, chimera studies implicated myeloid CD36 expression in RIC-mediated neurological recovery after ICH. Thus, RIC, a clinically well-tolerated therapy, noninvasively modulates innate immune responses to improve ICH outcomes. Moreover, immunometabolic changes may provide pharmacodynamic blood biomarkers to clinically monitor the therapeutic efficacy of RIC.
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Lee, Jungsoo, Heegoo Kim, Jinuk Kim, Won Hyuk Chang, and Yun-Hee Kim. "Multimodal Imaging Biomarker-Based Model Using Stratification Strategies for Predicting Upper Extremity Motor Recovery in Severe Stroke Patients." Neurorehabilitation and Neural Repair 36, no. 3 (December 31, 2021): 217–26. http://dx.doi.org/10.1177/15459683211070278.
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Background. Various prognostic biomarkers for upper extremity (UE) motor recovery after stroke have been reported. However, most have relatively low predictive accuracy in severe stroke patients. Objective. This study suggests an imaging biomarker-based model for effectively predicting UE recovery in severe stroke patients. Methods. Of 104 ischemic stroke patients screened, 42 with severe motor impairment were included. All patients underwent structural, diffusion, and functional magnetic resonance imaging at 2 weeks and underwent motor function assessments at 2 weeks and 3 months after stroke onset. According to motor function recovery at 3 months, patients were divided into good and poor subgroups. The value of multimodal imaging biomarkers of lesion load, lesion volume, white matter integrity, and cortical functional connectivity for motor recovery prediction was investigated in each subgroup. Results. Imaging biomarkers varied depending on recovery pattern. The integrity of the cerebellar tract ( P = .005, R 2 = .432) was the primary biomarker in the good recovery group. In contrast, the sensory-related corpus callosum tract ( P = .026, R 2 = .332) and sensory-related functional connectivity ( P = .001, R 2 = .531) were primary biomarkers in the poor recovery group. A prediction model was proposed by applying each biomarker in the subgroup to patients with different motor evoked potential responses ( P < .001, R 2 = .853, root mean square error = 5.28). Conclusions. Our results suggest an optimized imaging biomarker model for predicting UE motor recovery after stroke. This model can contribute to individualized management of severe stroke in a clinical setting.
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Malkki, Hemi. "Gut microbiota influence stroke recovery in mice." Nature Reviews Neurology 12, no. 5 (April 15, 2016): 252. http://dx.doi.org/10.1038/nrneurol.2016.52.
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O’Sullivan, Michael J., Xuqian Li, Dana Galligan, and Sarah T. Pendlebury. "Cognitive Recovery After Stroke: Memory." Stroke 54, no. 1 (January 2023): 44–54. http://dx.doi.org/10.1161/strokeaha.122.041497.
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Memory impairment occurs in over a third of patients after symptomatic stroke. Memory deficits rarely occur in isolation but are an important component of the poststroke cognitive syndrome because of the strong relationship with the risk of poststroke dementia. In this review, we summarize available data on impairment of episodic memory, with a particular emphasis on the natural history of memory impairment after stroke and the factors influencing trajectory informed by an updated systematic review. We next discuss the pathophysiology of memory impairment and mechanisms of both decline and recovery of function. We then turn to the practical issue of measurement of memory deficits after stroke, emerging biomarkers, and therapeutic approaches. Our review identifies critical gaps, particularly in studies of the natural history that properly map the long-term trajectory of memory and the associations with factors that modulate prognosis. Few studies have used advanced neuroimaging and this, in conjunction with other biomarker approaches, has the potential to provide a much richer understanding of the mechanisms at play and promising therapeutic avenues.
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Kemlin, C., E. Moulton, J. C. Lamy, and C. Rosso. "Resting motor threshold is a biomarker for motor stroke recovery." Annals of Physical and Rehabilitation Medicine 61 (July 2018): e26. http://dx.doi.org/10.1016/j.rehab.2018.05.057.
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Vernooij, Meike W. "Remote Brain Iron Accumulation: A Useful Biomarker for Stroke Recovery?" Radiology 291, no. 2 (May 2019): 449–50. http://dx.doi.org/10.1148/radiol.2019190336.
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Xu, Xiaoyun, Bethany Bass, William M. McKillop, Janina Mailloux, Tony Liu, Nicole M. Geremia, Todd Hryciw, and Arthur Brown. "Sox9 knockout mice have improved recovery following stroke." Experimental Neurology 303 (May 2018): 59–71. http://dx.doi.org/10.1016/j.expneurol.2018.02.001.
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Manwani, Bharti, Fudong Liu, Yan Xu, Rebecca Persky, Jun Li, and Louise D. McCullough. "Functional recovery in aging mice after experimental stroke." Brain, Behavior, and Immunity 25, no. 8 (November 2011): 1689–700. http://dx.doi.org/10.1016/j.bbi.2011.06.015.
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Abdullahi, Auwal, Steven Truijen, and Wim Saeys. "Neurobiology of Recovery of Motor Function after Stroke: The Central Nervous System Biomarker Effects of Constraint-Induced Movement Therapy." Neural Plasticity 2020 (June 15, 2020): 1–12. http://dx.doi.org/10.1155/2020/9484298.
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Recovery of motor function after stroke involves many biomarkers. This review attempts to identify the biomarker effects responsible for recovery of motor function following the use of Constraint-Induced Movement Therapy (CIMT) and discuss their implications for research and practice. From the studies reviewed, the biomarker effects identified include improved perfusion of motor areas and brain glucose metabolism; increased expression of proteins, namely, Brain-Derived Neurotrophic Factor (BDNF), Vascular Endothelial Growth Factor (VEGF), and Growth-Associated Protein 43 (GAP-43); and decreased level of Gamma-Aminobutyric Acid (GABA). Others include increased cortical activation, increased motor map size, and decreased interhemispheric inhibition of the ipsilesional hemisphere by the contralesional hemisphere. Interestingly, the biomarker effects correlated well with improved motor function. However, some of the biomarker effects have not yet been investigated in humans, and they require that CIMT starts early on poststroke. In addition, one study seems to suggest the combined use of CIMT with other rehabilitation techniques such as Transcortical Direct Stimulation (tDCs) in patients with chronic stroke to achieve the biomarker effects. Unfortunately, there are few studies in humans that implemented CIMT during early poststroke. Thus, it is important that more studies in humans are carried out to determine the biomarker effects of CIMT especially early on poststroke, when there is a greater opportunity for recovery. Furthermore, it should be noted that these effects are mainly in ischaemic stroke.
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Simpkins, Alexis N., Miroslaw Janowski, Helieh S. Oz, Jill Roberts, Gregory Bix, Sylvain Doré, and Ann M. Stowe. "Biomarker Application for Precision Medicine in Stroke." Translational Stroke Research 11, no. 4 (December 18, 2019): 615–27. http://dx.doi.org/10.1007/s12975-019-00762-3.
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AbstractStroke remains one of the leading causes of long-term disability and mortality despite recent advances in acute thrombolytic therapies. In fact, the global lifetime risk of stroke in adults over the age of 25 is approximately 25%, with 24.9 million cases of ischemic stroke and 18.7 million cases of hemorrhagic stroke reported in 2015. One of the main challenges in developing effective new acute therapeutics and enhanced long-term interventions for stroke recovery is the heterogeneity of stroke, including etiology, comorbidities, and lifestyle factors that uniquely affect each individual stroke survivor. In this comprehensive review, we propose that future biomarker studies can be designed to support precision medicine therapeutic interventions after stroke. The current challenges in defining ideal biomarkers for stroke are highlighted, including consideration of disease course, age, lifestyle factors, and subtypes of stroke. This overview of current clinical trials includes biomarker collection, and concludes with an example of biomarker design for aneurysmal subarachnoid hemorrhage. With the advent of “-omics” studies, neuroimaging, big data, and precision medicine, well-designed stroke biomarker trials will greatly advance the treatment of a disease that affects millions globally every year.
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Boyd, Lara A., Kathryn S. Hayward, Nick S. Ward, Cathy M. Stinear, Charlotte Rosso, Rebecca J. Fisher, Alexandre R. Carter, et al. "Biomarkers of stroke recovery: Consensus-based core recommendations from the Stroke Recovery and Rehabilitation Roundtable." International Journal of Stroke 12, no. 5 (July 2017): 480–93. http://dx.doi.org/10.1177/1747493017714176.
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The most difficult clinical questions in stroke rehabilitation are “What is this patient’s potential for recovery?” and “What is the best rehabilitation strategy for this person, given her/his clinical profile?” Without answers to these questions, clinicians struggle to make decisions regarding the content and focus of therapy, and researchers design studies that inadvertently mix participants who have a high likelihood of responding with those who do not. Developing and implementing biomarkers that distinguish patient subgroups will help address these issues and unravel the factors important to the recovery process. The goal of the present paper is to provide a consensus statement regarding the current state of the evidence for stroke recovery biomarkers. Biomarkers of motor, somatosensory, cognitive and language domains across the recovery timeline post-stroke are considered; with focus on brain structure and function, and exclusion of blood markers and genetics. We provide evidence for biomarkers that are considered ready to be included in clinical trials, as well as others that are promising but not ready and so represent a developmental priority. We conclude with an example that illustrates the utility of biomarkers in recovery and rehabilitation research, demonstrating how the inclusion of a biomarker may enhance future clinical trials. In this way, we propose a way forward for when and where we can include biomarkers to advance the efficacy of the practice of, and research into, rehabilitation and recovery after stroke.
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Boyd, Lara A., Kathryn S. Hayward, Nick S. Ward, Cathy M. Stinear, Charlotte Rosso, Rebecca J. Fisher, Alexandre R. Carter, et al. "Biomarkers of Stroke Recovery: Consensus-Based Core Recommendations from the Stroke Recovery and Rehabilitation Roundtable." Neurorehabilitation and Neural Repair 31, no. 10-11 (October 2017): 864–76. http://dx.doi.org/10.1177/1545968317732680.
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The most difficult clinical questions in stroke rehabilitation are “What is this patient’s potential for recovery?” and “What is the best rehabilitation strategy for this person, given her/his clinical profile?” Without answers to these questions, clinicians struggle to make decisions regarding the content and focus of therapy, and researchers design studies that inadvertently mix participants who have a high likelihood of responding with those who do not. Developing and implementing biomarkers that distinguish patient subgroups will help address these issues and unravel the factors important to the recovery process. The goal of the present paper is to provide a consensus statement regarding the current state of the evidence for stroke recovery biomarkers. Biomarkers of motor, somatosensory, cognitive and language domains across the recovery timeline post-stroke are considered; with focus on brain structure and function, and exclusion of blood markers and genetics. We provide evidence for biomarkers that are considered ready to be included in clinical trials, as well as others that are promising but not ready and so represent a developmental priority. We conclude with an example that illustrates the utility of biomarkers in recovery and rehabilitation research, demonstrating how the inclusion of a biomarker may enhance future clinical trials. In this way, we propose a way forward for when and where we can include biomarkers to advance the efficacy of the practice of, and research into, rehabilitation and recovery after stroke.
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Cassidy, Jessica M., Anirudh Wodeyar, Jennifer Wu, Kiranjot Kaur, Ashley K. Masuda, Ramesh Srinivasan, and Steven C. Cramer. "Low-Frequency Oscillations Are a Biomarker of Injury and Recovery After Stroke." Stroke 51, no. 5 (May 2020): 1442–50. http://dx.doi.org/10.1161/strokeaha.120.028932.
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Background and Purpose— Low-frequency oscillations reflect brain injury but also contribute to normal behaviors. We examined hypotheses relating electroencephalography measures, including low-frequency oscillations, to injury and motor recovery poststroke. Methods— Patients with stroke completed structural neuroimaging, a resting-state electroencephalography recording and clinical testing. A subset admitted to an inpatient rehabilitation facility also underwent serial electroencephalography recordings. The relationship that electroencephalography measures (power and coherence with leads overlying ipsilesional primary motor cortex [iM1]) had with injury and motor status was assessed, focusing on delta (1–3 Hz) and high-beta (20–30 Hz) bands. Results— Across all patients (n=62), larger infarct volume was related to higher delta band power in bilateral hemispheres and to higher delta band coherence between iM1 and bilateral regions. In chronic stroke, higher delta power bilaterally correlated with better motor status. In subacute stroke, higher delta coherence between iM1 and bilateral areas correlated with poorer motor status. These coherence findings were confirmed in serial recordings from 18 patients in an inpatient rehabilitation facility. Here, interhemispheric coherence between leads overlying iM1 and contralesional M1 was elevated at inpatient rehabilitation facility admission compared with healthy controls (n=22), declining to control levels over time. Decreases in interhemispheric coherence between iM1 and contralesional M1 correlated with better motor recovery. Conclusions— Delta band coherence with iM1 related to greater injury and poorer motor status subacutely, while delta band power related to greater injury and better motor status chronically. Low-frequency oscillations reflect both injury and recovery after stroke and may be useful biomarkers in stroke recovery and rehabilitation.
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Li, Jun, Matt Siegel, Mike Yuan, Zhiyuan Zeng, Laura Finnucan, Rebecca Persky, Patricia D. Hurn, and Louise D. McCullough. "Estrogen Enhances Neurogenesis and Behavioral Recovery after Stroke." Journal of Cerebral Blood Flow & Metabolism 31, no. 2 (October 13, 2010): 413–25. http://dx.doi.org/10.1038/jcbfm.2010.181.
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Stroke is a leading cause of permanent disability and death. It is well accepted that the principal mammalian estrogen (E2), 17-β estradiol, provides robust neuroprotection in a variety of brain injury models in animals of both sexes. E2 enhances neurogenesis after stroke in the subventricular zone; however, it is unknown if these cells survive long-term or enhance functional recovery. In this study, we examined stroke-induced neurogenesis in male, gonadally intact female, and ovariectomized female mice 2 and 6 weeks after stroke. Treatment with 17-β estradiol increased 5-bromo-2′-deoxyuridine-labeled cells at both time points in both the dentate gyrus and subventricular zone; the majority were colabeled with doublecortin at 2 weeks and with NeuN at 6 weeks. Stroke-induced neurogenesis was reduced in estrogen receptor knockout mice, as well as in mice lacking the gene for aromatase, which converts testosterone into E2. Improved behavioral deficits were seen in E2-treated mice, suggesting that E2-induced increases in poststroke neurogenesis contribute to poststroke recovery.
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Kim, Bokkyu, and Carolee Winstein. "Can Neurological Biomarkers of Brain Impairment Be Used to Predict Poststroke Motor Recovery? A Systematic Review." Neurorehabilitation and Neural Repair 31, no. 1 (August 19, 2016): 3–24. http://dx.doi.org/10.1177/1545968316662708.
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Background. There is growing interest to establish recovery biomarkers, especially neurological biomarkers, in order to develop new therapies and prediction models for the promotion of stroke rehabilitation and recovery. However, there is no consensus among the neurorehabilitation community about which biomarker(s) have the highest predictive value for motor recovery. Objective. To review the evidence and determine which neurological biomarker(s) meet the high evidence quality criteria for use in predicting motor recovery. Methods. We searched databases for prognostic neuroimaging/neurophysiological studies. Methodological quality of each study was assessed using a previously employed comprehensive 15-item rating system. Furthermore, we used the GRADE approach and ranked the overall evidence quality for each category of neurologic biomarker. Results. Seventy-one articles met our inclusion criteria; 5 categories of neurologic biomarkers were identified: diffusion tensor imaging (DTI), transcranial magnetic stimulation (TMS), functional magnetic resonance imaging (fMRI), conventional structural MRI (sMRI), and a combination of these biomarkers. Most studies were conducted with individuals after ischemic stroke in the acute and/or subacute stage (~70%). Less than one-third of the studies (21/71) were assessed with satisfactory methodological quality (80% or more of total quality score). Conventional structural MRI and the combination biomarker categories ranked “high” in overall evidence quality. Conclusions. There were 3 prevalent methodological limitations: ( a) lack of cross-validation, ( b) lack of minimal clinically important difference (MCID) for motor outcomes, and ( c) small sample size. More high-quality studies are needed to establish which neurological biomarkers are the best predictors of motor recovery after stroke. Finally, the quarter-century old methodological quality tool used here should be updated by inclusion of more contemporary methods and statistical approaches.
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Ray, Andreas M., Thiago D. C. Figueiredo, Eduardo López‐Larraz, Niels Birbaumer, and Ander Ramos‐Murguialday. "Brain oscillatory activity as a biomarker of motor recovery in chronic stroke." Human Brain Mapping 41, no. 5 (November 28, 2019): 1296–308. http://dx.doi.org/10.1002/hbm.24876.
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DeBoer, Scott R., Robert Hubbard, Mahlet Mersha, Gabriel Pinilla Monsalve, Stefan Winter, and Steven R. Zeiler. "Enhanced Spontaneous Motor Recovery After Stroke in Mice Treated With Cerebrolysin." Neurorehabilitation and Neural Repair 35, no. 6 (May 6, 2021): 525–33. http://dx.doi.org/10.1177/15459683211000734.
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Background Motor recovery after stroke in humans and in rodent models is time sensitive. Recovery in patients is a result of biological spontaneous recovery via endogenous repair mechanisms and is likely improved by enhancing the synaptic plasticity required for endogenous repair. Cerebrolysin is a polypeptide preparation known to enhance neuroplasticity and may improve recovery in patients. In mice, we tested the hypothesis that Cerebrolysin can act poststroke to enhance both spontaneous and training-associated motor recovery. Methods Mice were trained to perform a skilled prehension task. We then induced a photothrombotic stroke in the caudal forelimb area, after which we retrained animals on the prehension task in the presence or absence of Cerebrolysin after a 2-day or 8-day delay. Mice received daily intraperitoneal Cerebrolysin or saline injections starting poststroke day 1 or poststroke day 7. Results Prior studies showed that poststroke recovery of prehension can occur if animals receive rehabilitative training during an early sensitive period but is incomplete if rehabilitative training is delayed. In contrast, we show complete recovery of prehension, despite a delay in rehabilitative training, when mice receive daily Cerebrolysin administration starting on poststroke day 1 or on poststroke day 8. When Cerebrolysin is given on poststroke day 1, recovery occurred even in the absence of training. Stroke volumes were similar across groups. Conclusions Poststroke Cerebrolysin administration leads to recovery of motor function independent of rehabilitative training without a protective effect on stroke volume. This is one of the first demonstrations of training-independent motor recovery in rodent stroke models.
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Kurisu, Kota, Zhen Zheng, Jong Youl Kim, Jian Shi, Atsushi Kanoke, Jialing Liu, Christine L. Hsieh, and Midori A. Yenari. "Triggering receptor expressed on myeloid cells-2 expression in the brain is required for maximal phagocytic activity and improved neurological outcomes following experimental stroke." Journal of Cerebral Blood Flow & Metabolism 39, no. 10 (December 7, 2018): 1906–18. http://dx.doi.org/10.1177/0271678x18817282.
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Triggering receptor expressed on myeloid cells-2 (TREM2) is an innate immune receptor that promotes phagocytosis by myeloid cells such as microglia and macrophages. We previously showed that TREM2 deficiency worsened outcomes from experimental stroke and impeded phagocytosis. However, myeloid cells participating in stroke pathology include both brain resident microglia and circulating macrophages. We now clarify whether TREM2 on brain microglia or circulating macrophages contribute to its beneficial role in ischemic stroke by generating bone marrow (BM) chimeric mice. BM chimera mice from TREM2 knockout (KO) or wild type (Wt) mice were used as donor and recipient mice. Mice were subjected to experimental stroke, and neurological function and infarct volume were assessed. Mice with intact TREM2 in brain microglia showed better neurological recovery and reduced infarct volumes, compared with mice lacking microglial TREM2. Myeloid cell activation and numbers of phagocytes were decreased in mice lacking brain TREM2, compared with mice with intact brain TREM2. These results suggest that TREM2 expression is important for post-stroke recovery, and that TREM2 expression on brain resident microglia is more essential to this recovery, than that of circulating macrophages. These findings might suggest a new therapeutic target for cerebrovascular diseases.
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Ollen-Bittle, Nikita, Austyn D. Roseborough, Wenxuan Wang, Jeng-liang D. Wu, and Shawn N. Whitehead. "Mechanisms and Biomarker Potential of Extracellular Vesicles in Stroke." Biology 11, no. 8 (August 18, 2022): 1231. http://dx.doi.org/10.3390/biology11081231.
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Stoke is a prevalent and devastating neurologic condition with limited options for therapeutic management. Since brain tissue is rarely accessible clinically, peripheral biomarkers for the central nervous system’s (CNS’s) cellular response to stroke may prove critical for increasing our understanding of stroke pathology and elucidating novel therapeutic targets. Extracellular vesicles (EVs) are cell-derived, membrane-enclosed vesicles secreted by all cell types within the CNS that can freely pass the blood-brain barrier (BBB) and contain unique markers and content linked to their cell of origin. These unique qualities make brain-derived EVs novel candidates for non-invasive blood-based biomarkers of both cell specificity and cell physiological state during the progression of stroke and recovery. While studies are continuously emerging that are assessing the therapeutic potential of EVs and profiling EV cargo, a vast minority of these studies link EV content to specific cell types. A better understanding of cell-specific EV release during the acute, subacute, and chronic stages of stroke is needed to further elucidate the cellular processes responsible for stroke pathophysiology. Herein, we outline what is known about EV release from distinct cell types of the CNS during stroke and the potential of these EVs as peripheral biomarkers for cellular function in the CNS during stroke.
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Wang, Ya-chao, Xuan Li, Yuntian Shen, Jingjun Lyu, Huaxin Sheng, Wulf Paschen, and Wei Yang. "PERK (Protein Kinase RNA-Like ER Kinase) Branch of the Unfolded Protein Response Confers Neuroprotection in Ischemic Stroke by Suppressing Protein Synthesis." Stroke 51, no. 5 (May 2020): 1570–77. http://dx.doi.org/10.1161/strokeaha.120.029071.
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Background and Purpose— Ischemic stroke impairs endoplasmic reticulum (ER) function, causes ER stress, and activates the unfolded protein response. The unfolded protein response consists of 3 branches controlled by ER stress sensor proteins, which include PERK (protein kinase RNA-like ER kinase). Activated PERK phosphorylates eIF2α (eukaryotic initiation factor 2 alpha), resulting in inhibition of global protein synthesis. Here, we aimed to clarify the role of the PERK unfolded protein response branch in stroke. Methods— Neuron-specific and tamoxifen-inducible PERK conditional knockout (cKO) mice were generated by cross-breeding Camk2a-CreERT2 with Perk f/f mice. Transient middle cerebral artery occlusion was used to induce stroke. Short- and long-term stroke outcomes were evaluated. Protein synthesis in the brain was assessed using a surface-sensing-of-translation approach. Results— After tamoxifen-induced deletion of Perk in forebrain neurons was confirmed in PERK-cKO mice, PERK-cKO and control mice were subjected to transient middle cerebral artery occlusion and 3 days or 3 weeks recovery. PERK-cKO mice had larger infarcts and worse neurological outcomes compared with control mice, suggesting that PERK-induced eIF2α phosphorylation and subsequent suppression of translation protects neurons from ischemic stress. Indeed, better stroke outcomes were observed in PERK-cKO mice that received postischemic treatment with salubrinal, which can restore the ischemia-induced increase in phosphorylated eIF2α in these mice. Finally, our data showed that post-treatment with salubrinal improved functional recovery after stroke. Conclusions— Here, we presented the first evidence that postischemic suppression of translation induced by PERK activation promotes recovery of neurological function after stroke. This confirms and further extends our previous observations that recovery of ER function impaired by ischemic stress critically contributes to stroke outcome. Therefore, future research should include strategies to improve stroke outcome by targeting unfolded protein response branches to restore protein homeostasis in neurons.
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Ritzel, Rodney M., Anita R. Patel, Monica Spychala, Rajkumar Verma, Joshua Crapser, Edward C. Koellhoffer, Anna Schrecengost, et al. "Multiparity improves outcomes after cerebral ischemia in female mice despite features of increased metabovascular risk." Proceedings of the National Academy of Sciences 114, no. 28 (June 23, 2017): E5673—E5682. http://dx.doi.org/10.1073/pnas.1607002114.
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Females show a varying degree of ischemic sensitivity throughout their lifespan, which is not fully explained by hormonal or genetic factors. Epidemiological data suggest that sex-specific life experiences such as pregnancy increase stroke risk. This work evaluated the role of parity on stroke outcome. Age-matched virgin (i.e., nulliparous) and multiparous mice were subjected to 60 min of reversible middle cerebral artery occlusion and evaluated for infarct volume, behavioral recovery, and inflammation. Using an established mating paradigm, fetal microchimeric cells present in maternal mice were also tracked after parturition and stroke. Parity was associated with sedentary behavior, weight gain, and higher triglyceride and cholesterol levels. The multiparous brain exhibited features of immune suppression, with dampened baseline microglial activity. After acute stroke, multiparous mice had smaller infarcts, less glial activation, and less behavioral impairment in the critical recovery window of 72 h. Behavioral recovery was significantly better in multiparous females compared with nulliparous mice 1 mo after stroke. This recovery was accompanied by an increase in poststroke angiogenesis that was correlated with improved performance on sensorimotor and cognitive tests. Multiparous mice had higher levels of VEGF, both at baseline and after stroke. GFP+ fetal cells were detected in the blood and migrated to areas of tissue injury where they adopted endothelial morphology 30 d after injury. Reproductive experience has profound and complex effects on neurovascular health and disease. Inclusion of female mice with reproductive experience in preclinical studies may better reflect the life-long patterning of ischemic stroke risk in women.
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STANESCU, Ioana C., Angelo C. BULBOACA, Gabriela B. DOGARU, Gabriel GUSETU, and Dana M. FODOR. "Predictors for early motor improvement in patients with ischemic stroke." Balneo Research Journal 10, Vol.10, No.3 (September 3, 2019): 236–42. http://dx.doi.org/10.12680/balneo.2019.263.
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Disability as a stroke consequence is reported by 3% males and 2% females in general population. Motor deficits are common in stroke patients, but their complete recovery is seen only in a minority of cases. Assessment of motor deficits uses clinical methods, especially standardized scales, but also electrophysiological and imagistic methods. The motor recovery is a continuous process, maximal in the first month after stroke, decreasing gradually over the first 6 months. Most powerful predictors for motor recovery are clinical parameters: severity of motor deficit, onset of first voluntary movements after stroke in the first 48-72 hours, a continuous improvement in motor function during the first 8 weeks, a good postural control during the first month, young age, male sex, left hemispheric stroke and absence of other neurological impairments are strong positive predictors. Presence of motor-evoked potentials in paretic muscles and imagistic parameters as location, stroke volume and motor pathways integrity are paraclinical predictors for recovery. There are no specific biomarker which is efficient in predicting recovery. In patients with poor chances for recovery according to actual predictors, the development of more precise algorithms to assess functional outcome is needed, in order to support the choice of appropriate methods and intensity of rehabilitation treatment. Key words: ischemic stroke rehabilitation, functional assessment, motor improvement, recovery predictors, prognostic factors,
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Kawano, Teiji, Noriaki Hattori, Yutaka Uno, Megumi Hatakenaka, Hajime Yagura, Hiroaki Fujimoto, Tomomi Yoshioka, et al. "Electroencephalographic Phase Synchrony Index as a Biomarker of Poststroke Motor Impairment and Recovery." Neurorehabilitation and Neural Repair 34, no. 8 (July 21, 2020): 711–22. http://dx.doi.org/10.1177/1545968320935820.
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Background. Motor recovery after stroke is of great clinical interest. Besides magnetic resonance imaging functional connectivity, electroencephalographic synchrony is also an available biomarker. However, the clinical relevance of electroencephalographic synchrony in hemiparesis has not been fully understood. Objective. We aimed to demonstrate the usefulness of the phase synchrony index (PSI) by showing associations between the PSI and poststroke outcome in patients with hemiparesis. Methods. This observational study included 40 participants with cortical ischemic stroke (aged 69.8 ± 13.8 years) and 22 healthy controls (aged 66.9 ± 6.5 years). Nineteen-channel electroencephalography was recorded at 36.9 ± 11.8 days poststroke. Upper extremity Fugl-Meyer scores were assessed at the time of admission/before discharge (FM-UE1/FM-UE2; 32.6 ± 12.3/121.0 ± 44.7 days poststroke). Then, correlations between the PSIs and FM-UE1 as well as impairment reduction after rehabilitation (FM-UEgain) were analyzed. Results. The interhemispheric PSI (alpha band) between the primary motor areas (M1s) was lower in patients than in controls and was selectively correlated with FM-UE1 ( P = .001). In contrast, the PSI (theta band) centered on the contralesional M1 was higher in patients than in controls and was selectively correlated with FM-UEgain ( P = .003). These correlations remained significant after adjusting for confounding factors (age, time poststroke, National Institute of Health Stroke Scale, and lesion volume). Furthermore, the latter correlation was significant in severely impaired patients (FM-UE1 ≤ 10). Conclusions. This study showed that the PSIs were selectively correlated with motor impairment and recovery. Therefore, the PSIs may be potential biomarkers in persons with a hemispheric infarction.
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Pintana, Hiranya, Grazyna Lietzau, Ingrid Lovise Augestad, Fausto Chiazza, Thomas Nyström, Cesare Patrone, and Vladimer Darsalia. "Obesity-induced type 2 diabetes impairs neurological recovery after stroke in correlation with decreased neurogenesis and persistent atrophy of parvalbumin-positive interneurons." Clinical Science 133, no. 13 (July 1, 2019): 1367–86. http://dx.doi.org/10.1042/cs20190180.
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Abstract Type 2 diabetes (T2D) hampers stroke recovery though largely undetermined mechanisms. Few preclinical studies have investigated the effect of genetic/toxin-induced diabetes on long-term stroke recovery. However, the effects of obesity-induced T2D are mostly unknown. We aimed to investigate whether obesity-induced T2D worsens long-term stroke recovery through the impairment of brain’s self-repair mechanisms – stroke-induced neurogenesis and parvalbumin (PV)+ interneurons-mediated neuroplasticity. To mimic obesity-induced T2D in the middle-age, C57bl/6j mice were fed 12 months with high-fat diet (HFD) and subjected to transient middle cerebral artery occlusion (tMCAO). We evaluated neurological recovery by upper-limb grip strength at 1 and 6 weeks after tMCAO. Gray and white matter damage, stroke-induced neurogenesis, and survival and potential atrophy of PV-interneurons were quantitated by immunohistochemistry (IHC) at 2 and 6 weeks after tMCAO. Obesity/T2D impaired neurological function without exacerbating brain damage. Moreover, obesity/T2D diminished stroke-induced neural stem cell (NSC) proliferation and neuroblast formation in striatum and hippocampus at 2 weeks after tMCAO and abolished stroke-induced neurogenesis in hippocampus at 6 weeks. Finally, stroke resulted in the atrophy of surviving PV-interneurons 2 weeks after stroke in both non-diabetic and obese/T2D mice. However, after 6 weeks, this effect selectively persisted in obese/T2D mice. We show in a preclinical setting of clinical relevance that obesity/T2D impairs neurological functions in the stroke recovery phase in correlation with reduced neurogenesis and persistent atrophy of PV-interneurons, suggesting impaired neuroplasticity. These findings shed light on the mechanisms behind impaired stroke recovery in T2D and could facilitate the development of new stroke rehabilitative strategies for obese/T2D patients.
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Kraft, Andrew W., Adam Q. Bauer, Joseph P. Culver, and Jin-Moo Lee. "Sensory deprivation after focal ischemia in mice accelerates brain remapping and improves functional recovery through Arc-dependent synaptic plasticity." Science Translational Medicine 10, no. 426 (January 31, 2018): eaag1328. http://dx.doi.org/10.1126/scitranslmed.aag1328.
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Recovery after stroke, a major cause of adult disability, is often unpredictable and incomplete. Behavioral recovery is associated with functional reorganization (remapping) in perilesional regions, suggesting that promoting this process might be an effective strategy to enhance recovery. However, the molecular mechanisms underlying remapping after brain injury and the consequences of its modulation are poorly understood. Focal sensory loss or deprivation has been shown to induce remapping in the corresponding brain areas through activity-regulated cytoskeleton-associated protein (Arc)–mediated synaptic plasticity. We show that targeted sensory deprivation via whisker trimming in mice after induction of ischemic stroke in the somatosensory cortex representing forepaw accelerates remapping into the whisker barrel cortex and improves sensorimotor recovery. These improvements persisted even after focal sensory deprivation ended (whiskers allowed to regrow). Mice deficient in Arc, a gene critical for activity-dependent synaptic plasticity, failed to remap or recover sensorimotor function. These results indicate that post-stroke remapping occurs through Arc-mediated synaptic plasticity and is required for behavioral recovery. Furthermore, our findings suggest that enhancing perilesional cortical plasticity via focal sensory deprivation improves recovery after ischemic stroke in mice.
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Liauw, Jason, Stanley Hoang, Michael Choi, Cagla Eroglu, Matthew Choi, Guo-hua Sun, Matthew Percy, et al. "Thrombospondins 1 and 2 are Necessary for Synaptic Plasticity and Functional Recovery after Stroke." Journal of Cerebral Blood Flow & Metabolism 28, no. 10 (July 2, 2008): 1722–32. http://dx.doi.org/10.1038/jcbfm.2008.65.
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Thrombospondins 1 and 2 (TSP-1/2) belong to a family of extracellular glycoproteins with angiostatic and synaptogenic properties. Although TSP-1/2 have been postulated to drive the resolution of postischemic angiogenesis, their role in synaptic and functional recovery is unknown. We investigated whether TSP-1/2 are necessary for synaptic and motor recovery after stroke. Focal ischemia was induced in 8- to 12-week-old wild-type (WT) and TSP-1/2 knockout (KO) mice by unilateral occlusion of the distal middle cerebral artery and the common carotid artery (CCA). Thrombospondins 1 and 2 increased after stroke, with both TSP-1 and TSP-2 colocalizing mostly to astrocytes. Wild-type and TSP-1/2 KO mice were compared in angiogenesis, synaptic density, axonal sprouting, infarct size, and functional recovery at different time points after stroke. Using the tongue protrusion test of motor function, we observed that TSP-1/2 KO mice exhibited significant deficit in their ability to recover function ( P < 0.05) compared with WT mice. No differences were found in infarct size and blood vessel density between the two groups after stroke. However, TSP-1/2 KO mice exhibited significant synaptic density and axonal sprouting deficits. Deficiency of TSP-1/2 leads to impaired recovery after stroke mainly due to the role of these proteins in synapse formation and axonal outgrowth.
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Lie, Maria EK, Emma K. Gowing, Nina B. Johansen, Nils Ole Dalby, Louise Thiesen, Petrine Wellendorph, and Andrew N. Clarkson. "GAT3 selective substrate l-isoserine upregulates GAT3 expression and increases functional recovery after a focal ischemic stroke in mice." Journal of Cerebral Blood Flow & Metabolism 39, no. 1 (November 21, 2017): 74–88. http://dx.doi.org/10.1177/0271678x17744123.
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Ischemic stroke triggers an elevation in tonic GABA inhibition that impairs the ability of the brain to form new structural and functional cortical circuits required for recovery. This stroke-induced increase in tonic inhibition is caused by impaired GABA uptake via the glial GABA transporter GAT3, highlighting GAT3 as a novel target in stroke recovery. Using a photothrombotic stroke mouse model, we show that GAT3 protein levels are decreased in peri-infarct tissue from 6 h to 42 days post-stroke. Prior studies have shown that GAT substrates can increase GAT surface expression. Therefore, we aimed to assess whether the GAT3 substrate, L-isoserine, could increase post-stroke functional recovery. L-Isoserine (38 µM or 380 µM) administered directly into the infarct from day 5 to 32 post-stroke, significantly increased motor performance in the grid-walking and cylinder tasks in a concentration-dependent manner, without affecting infarct volumes. Additionally, L-isoserine induced a lasting increase in GAT3 expression in peri-infarct regions accompanied by a small decrease in GFAP expression. This study is the first to show that a GAT3 substrate can increase GAT3 expression and functional recovery after focal ischemic stroke following a delayed long-term treatment. We propose that enhancing GAT3-mediated uptake dampens tonic inhibition and promotes functional recovery after stroke.
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Clarkson, Andrew N., Kim Parker, Michael Nilsson, F. Rohan Walker, and Emma K. Gowing. "Combined Ampakine and BDNF Treatments Enhance Poststroke Functional Recovery in Aged Mice via AKT-CREB Signaling." Journal of Cerebral Blood Flow & Metabolism 35, no. 8 (March 11, 2015): 1272–79. http://dx.doi.org/10.1038/jcbfm.2015.33.
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Cerebral ischemia results in damage to neuronal circuits and lasting impairment in function. We have previously reported that stimulation of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors with the ampakine, CX1837, increases brain-derived neurotrophic factor (BDNF) levels and affords significant motor recovery after stroke in young mice. Here, we investigated whether administration of CX1837 in aged (24 months old) mice was equally effective. In a model of focal ischemia, administration of CX1837 from 5 days after stroke resulted in a small gain of motor function by week 6 after stroke. Mice that received a local delivery of BDNF via hydrogel implanted into the stroke cavity also showed a small gain of function from 4 to 6 weeks after stroke. Combining both treatments, however, resulted in a marked improvement in motor function from 2 weeks after insult. Assessment of peri-infarct tissue 2 weeks after stroke revealed a significant increase in p-AKT and p-CREB after the combined drug treatment. Using the pan-AKT inhibitor, GSK-690693, or deletion of CREB from forebrain neurons using the CREB-flox/CAMKii-cre mice, we were able to block the recovery of motor function. These data suggest that combined CX1837 and local delivery of BDNF are required to achieve maximal functional recovery after stroke in aged mice, and is occurring via the AKT-GSK3-CREB signaling pathway.
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Borowicz, Wojciech, Marta Szczepańska, and Joanna Rosińczuk. "C-Reactive protein as a biomarker affecting neurorehabilitation outcomes in post-stroke patients: state of knowledge and global trends in research." Journal of Education, Health and Sport 13, no. 4 (February 16, 2023): 92–107. http://dx.doi.org/10.12775/jehs.2023.13.04.010.
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Background: C-reactive protein (CRP) is a commonly determined biomarker of inflammation and may reflect the progression of a vascular disease. CRP values within 12 to 24 hours of stroke symptom onset are an independent predictor of adverse functional outcome in terms of the level of motor recovery in the first year of follow-up. Objective: This study aims to provide a complementary analysis of the scientific literature and critically review studies on the use of CRP as a potential biomarker associated with stroke and affecting the achievement of neurorehabilitation progress in post-stroke patients. Methods: This critical review of the literature was prepared based on the following inclusion criteria: (1) original research, (2) studies indexed in PubMed, Scopus and PEDro databases, (3) full-text articles in English, (4) papers published in 2012 – 2022, and (5) papers addressing the use of PCR assay as a biomarker of rehabilitation effectiveness. Results: Based on a review of PubMed, Scopus and PEDro databases, 47, 56 and 9 papers, respectively, were selected based on precisely selected keywords and included in full for further full text review. In this review, the most important scientific rationale was included in response to the aim of this paper. Summary: Recognition of the role of inflammatory and immunological factors in the development of atherosclerosis and the occurrence of ischaemic stroke provides scope for the search for new methods of stroke risk assessment and the development of new methods to prevent stroke. Further empirical validation and unequivocal demonstration of the levels of CRP as a potential marker that affects the health status of a post-stroke patient are needed to ensure the greatest possible level of motor recovery and ability to function independently in terms of all activities of daily living.
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Gandin, Carine, Catherine Widmann, Michel Lazdunski, and Catherine Heurteaux. "MLC901 Favors Angiogenesis and Associated Recovery after Ischemic Stroke in Mice." Cerebrovascular Diseases 42, no. 1-2 (2016): 139–54. http://dx.doi.org/10.1159/000444810.
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Background: There is increasing evidence that angiogenesis, through new blood vessel formation, results in improved collateral circulation and may impact the long-term recovery of patients. In this study, we first investigated the preventive action of a 5-week pretreatment of MLC901, an herbal extract preparation derived from Chinese medicine, against the deleterious effects of ischemic stroke and its effects on angiogenesis in a model of focal ischemia in mice. Methods: The stroke model was induced by 60 min of middle cerebral artery occlusion followed by reperfusion. MLC901 was administered in the drinking water of animals (6 g/l) for 5 weeks before ischemia and then during reperfusion. Results: MLC901 treatment increased the survival rate, reduced the cerebral infarct area and attenuated the blood brain barrier leakage as well as the neurologic dysfunction following ischemia and reperfusion. We provide evidence that MLC901 enhances endothelial cell proliferation and angiogenesis by increasing the number of neocortical vessels in the infarcted area. MLC901 regulates the expression of hypoxic inducible factor 1α and its downstream targets such as vascular endothelial growth factor and angiopoietins 1 and 2. This work also shows that erythropoietin is an important player in the enhancement of angiogenesis by MLC901. Conclusions: These results demonstrate therapeutic properties of MLC901, in addition to those previously described, in stimulating revascularization, neuroprotection and repair of the neurovascular unit after ischemic stroke.
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Houlton, Josh, Lisa Y. Y. Zhou, Deanna Barwick, Emma K. Gowing, and Andrew N. Clarkson. "Stroke Induces a BDNF-Dependent Improvement in Cognitive Flexibility in Aged Mice." Neural Plasticity 2019 (May 5, 2019): 1–14. http://dx.doi.org/10.1155/2019/1460890.
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Stroke remains a leading cause of disability worldwide. Recently, we have established an animal model of stroke that results in delayed impairment in spatial memory, allowing us to better investigate cognitive deficits. Young and aged brains show different recovery profiles after stroke; therefore, we assessed aged-related differences in poststroke cognition. As neurotrophic support diminishes with age, we also investigated the involvement of brain-derived neurotrophic factor (BDNF) in these differences. Young (3-6 months old) and aged (16-21 months old) mice were trained in operant touchscreen chambers to complete a visual pairwise discrimination (VD) task. Stroke or sham surgery was induced using the photothrombotic model to induce a bilateral prefrontal cortex stroke. Five days poststroke, an additional cohort of aged stroke animals were treated with intracerebral hydrogels loaded with the BDNF decoy, TrkB-Fc. Following treatment, animals underwent the reversal and rereversal task to identify stroke-induced cognitive deficits at days 17 and 37 poststroke, respectively. Assessment of sham animals using Cox regression and log-rank analyses showed aged mice exhibit an increased impairment on VD reversal and rereversal learning compared to young controls. Stroke to young mice revealed no impairment on either task. In contrast, stroke to aged mice facilitated a significant improvement in reversal learning, which was dampened in the presence of the BDNF decoy, TrkB-Fc. In addition, aged stroke control animals required significantly less consecutive days and correction trials to master the reversal task, relative to aged shams, an effect dampened by TrkB-Fc. Our findings support age-related differences in recovery of cognitive function after stroke. Interestingly, aged stroke animals outperformed their sham counterparts, suggesting reopening of a critical window for recovery that is being mediated by BDNF.
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Puig, Josep, Gerard Blasco, Gottfried Schlaug, Cathy M. Stinear, Pepus Daunis-i-Estadella, Carles Biarnes, Jaume Figueras, et al. "Diffusion tensor imaging as a prognostic biomarker for motor recovery and rehabilitation after stroke." Neuroradiology 59, no. 4 (March 14, 2017): 343–51. http://dx.doi.org/10.1007/s00234-017-1816-0.
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Vahdat, Shahabeddin, Arjun Vivek Pendharkar, Terrance Chiang, Sean Harvey, Haruto Uchino, Zhijuan Cao, Anika Kim, et al. "Brain-wide neural dynamics of poststroke recovery induced by optogenetic stimulation." Science Advances 7, no. 33 (August 2021): eabd9465. http://dx.doi.org/10.1126/sciadv.abd9465.
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Poststroke optogenetic stimulations can promote functional recovery. However, the circuit mechanisms underlying recovery remain unclear. Elucidating key neural circuits involved in recovery will be invaluable for translating neuromodulation strategies after stroke. Here, we used optogenetic functional magnetic resonance imaging to map brain-wide neural circuit dynamics after stroke in mice treated with and without optogenetic excitatory neuronal stimulations in the ipsilesional primary motor cortex (iM1). We identified key sensorimotor circuits affected by stroke. iM1 stimulation treatment restored activation of the ipsilesional corticothalamic and corticocortical circuits, and the extent of activation was correlated with functional recovery. Furthermore, stimulated mice exhibited higher expression of axonal growth–associated protein 43 in the ipsilesional thalamus and showed increased Synaptophysin+/channelrhodopsin+ presynaptic axonal terminals in the corticothalamic circuit. Selective stimulation of the corticothalamic circuit was sufficient to improve functional recovery. Together, these findings suggest early involvement of corticothalamic circuit as an important mediator of poststroke recovery.
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Wei, Zheng Zachory, Dongdong Chen, Li-Ping Liu, Xiaohuan Gu, Weiwei Zhong, Yong-Bo Zhang, Yongjun Wang, Shan Ping Yu, and Ling Wei. "Enhanced Neurogenesis and Collaterogenesis by Sodium Danshensu Treatment After Focal Cerebral Ischemia in Mice." Cell Transplantation 27, no. 4 (April 2018): 622–36. http://dx.doi.org/10.1177/0963689718771889.
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Ischemic stroke remains a serious threat to human life. There are limited effective therapies for the treatment of stroke. We have previously demonstrated that angiogenesis and neurogenesis in the brain play an important role in functional recovery following ischemic stroke. Recent studies indicate that increased arteriogenesis and collateral circulation are determining factors for restoring reperfusion and outcomes of stroke patients. Danshensu, the Salvia miltiorrhiza root extract, is used in treatments of various human ischemic events in traditional Chinese medicine. Its therapeutic mechanism, however, is not well clarified. Due to its proposed effect on angiogenesis and arteriogenesis, we hypothesized that danshensu could benefit stroke recovery through stimulating neurogenesis and collaterogenesis in the post-ischemia brain. Focal ischemic stroke targeting the right sensorimotor cortex was induced in wild-type C57BL6 mice and transgenic mice expressing green fluorescent protein (GFP) to label smooth muscle cells of brain arteries. Sodium danshensu (SDS, 700 mg/kg) was administered intraperitoneally (i.p.) 10 min after stroke and once daily until animals were sacrificed. To label proliferating cells, 5-bromo-2′-deoxyuridine (BrdU; 50 mg/kg, i.p.) was administered, starting on day 3 after ischemia and continued once daily until sacrifice. At 14 days after stroke, SDS significantly increased the expression of vascular endothelial growth factor (VEGF), stromal-derived factor-1 (SDF-1), brain-derived neurotrophic factor (BDNF), and endothelial nitric oxide synthase (eNOS) in the peri-infarct region. SDS-treated animals showed increased number of doublecortin (DCX)-positive cells. Greater numbers of proliferating endothelial cells and smooth muscle cells were detected in SDS-treated mice 21 days after stroke in comparison with vehicle controls. The number of newly formed neurons labeled by NeuN and BrdU antibodies increased in SDS-treated mice 28 days after stroke. SDS significantly increased the newly formed arteries and the diameter of collateral arteries, leading to enhanced local cerebral blood flow recovery after stroke. These results suggest that systemic sodium danshensu treatment shows significant regenerative effects in the post-ischemic brain, which may benefit long-term functional recovery from ischemic stroke.
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Li, Yanzheng, Wei Wang, Hang Yang, Weiheng Guo, Jingyu Feng, Dejiu Yang, Li Guo, and Guojun Tan. "Negative correlation between early recovery and lipoprotein-associated phospholipase A2 levels after intravenous thrombolysis." Journal of International Medical Research 50, no. 4 (April 2022): 030006052210933. http://dx.doi.org/10.1177/03000605221093303.
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Objective Lipoprotein-associated phospholipase A2 (Lp-PLA2) is considered a biomarker for systemic inflammation and the risk of myocardial infarction and stroke. However, little is known about the effect of acute vascular events on marker levels. The purpose of this study was to assess the potential association of early recovery with Lp-PLA2 levels in patients with acute ischemic stroke (AIS) after intravenous thrombolysis (IVT). Methods Forty-three consecutive AIS patients who had their first stroke and were hospitalized within 5 hours of the onset of stroke were enrolled. All patients were treated with IVT using alteplase or urokinase. Plasma Lp-PLA2 levels were measured within 24 hours after IVT. Variables that showed a significant association with Lp-PLA2 in univariate analysis were included in the multivariate ordered logistic regression model. Results Early recovery was associated with Lp-PLA2 levels after IVT, and Lp-PLA2 levels tended to decrease with increased probability of early recovery. This study is the first to report a negative correlation between early recovery and Lp-PLA2 levels after IVT. Conclusion Early recovery after IVT was negatively correlated with Lp-PLA2 A2 levels.
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van Nieuwenhuijzen, Petra S., Kim Parker, Vivian Liao, Josh Houlton, Hye-Lim Kim, Graham A. R. Johnston, Jane R. Hanrahan, Mary Chebib, and Andrew N. Clarkson. "Targeting GABAC Receptors Improves Post-Stroke Motor Recovery." Brain Sciences 11, no. 3 (March 2, 2021): 315. http://dx.doi.org/10.3390/brainsci11030315.
Full textAbstract:
Ischemic stroke remains a leading cause of disability worldwide, with limited treatment options available. This study investigates GABAC receptors as novel pharmacological targets for stroke recovery. The expression of ρ1 and ρ2 mRNA in mice were determined in peri-infarct tissue following photothrombotic motor cortex stroke. (R)-4-amino-cyclopent-1-enyl butylphosphinic acid (R)-4-ACPBPA and (S)-4-ACPBPA were assessed using 2-elecotrode voltage electrophysiology in Xenopus laevis oocytes. Stroke mice were treated for 4 weeks with either vehicle, the α5-selective negative allosteric modulator, L655,708, or the ρ1/2 antagonists, (R)-4-ACPBPA and (S)-4-ACPBPA respectively from 3 days post-stroke. Infarct size and expression levels of GAT3 and reactive astrogliosis were determined using histochemistry and immunohistochemistry respectively, and motor function was assessed using both the grid-walking and cylinder tasks. After stroke, significant increases in ρ1 and ρ2 mRNAs were observed on day 3, with ρ2 showing a further increase on day 7. (R)- and (S)-4-ACPBPA are both potent antagonists at ρ2 and only weak inhibitors of α5β2γ2 receptors. Treatment with either L655,708, (S)-4-ACPBPA (ρ1/2 antagonist; 5 mM only), or (R)-4-ACPBPA (ρ2 antagonist; 2.5 and 5 mM) from 3 days after stroke resulted in a significant improvement in motor recovery on the grid-walking task, with L655,708 and (R)-4-ACPBPA also showing an improvement in the cylinder task. Infarct size was unaffected, and only (R)-4-ACPBPA significantly increased peri-infarct GAT3 expression and decreased the level of reactive astrogliosis. Importantly, inhibiting GABAC receptors affords significant improvement in motor function after stroke. Targeting the ρ-subunit could provide a novel delayed treatment option for stroke recovery.
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Sharma, Rishi, Abigail Chischolm, Meet Parikh, Adnan I. Qureshi, Pradeep Sahota, and Mahesh M. Thakkar. "Ischemic Stroke Disrupts Sleep Homeostasis in Middle-Aged Mice." Cells 11, no. 18 (September 9, 2022): 2818. http://dx.doi.org/10.3390/cells11182818.
Full textAbstract:
Sleep disturbances, including insomnia and excessive daytime sleepiness, are highly prevalent in patients with ischemic stroke (IS), which severely impacts recovery and rehabilitation efforts. However, how IS induces sleep disturbances is unclear. Three experiments were performed on middle-aged C57BL/6J mice, instrumented with sleep recording electrodes and/or subjected to 1 h of middle cerebral artery (MCAO; Stroke group) or sham (Sham group) occlusion to induce IS. After 48 h of reperfusion (a) experiment 1 verified sensorimotor deficit (using Garcia scale) and infarction (using TTC staining) in this mouse model; (b) experiment 2 examined the effects of IS on the quality (sleep latency and NREM delta power) and quantity (duration) of sleep; and (c) experiment 3 determined the effects of IS on sleep homeostasis using sleep deprivation (SD) and recovery sleep (RS) paradigm. Stroke mice display (a) a significant correlation between sensorimotor deficit and cerebral infarction; (b) insomnia-like symptoms (increased sleep latency, reduced NREM duration and delta power) during the light (inactive) period and daytime sleepiness-like symptoms during the dark (active) period mimicking sleep in IS patients; and (c) impairments in the markers of sleep pressure (during SD) and sleep dissipation (during RS). Our results suggest that IS disrupts sleep homeostasis to cause sleep disturbances.
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Nygren, Josefine, and Tadeusz Wieloch. "Enriched Environment Enhances Recovery of Motor Function after Focal Ischemia in Mice, and Downregulates the Transcription Factor NGFI-A." Journal of Cerebral Blood Flow & Metabolism 25, no. 12 (May 25, 2005): 1625–33. http://dx.doi.org/10.1038/sj.jcbfm.9600157.
Full textAbstract:
The purpose of this study was to investigate the effect of enriched environment on motor function after experimental stroke in mice, and to determine whether time in enriched environment affects functional recovery. Earlier investigations have shown that rats placed in an enriched environment after focal ischemia, remarkably improve motor function, but similar observations in mice have not been reported. In this study, we show that placing mice in an enriched environment for 3 h daily for 2 weeks, after transient (50 mins) occlusion of the middle cerebral artery, enhanced neurologic outcome. Continuous postischemic housing in the enriched environment likewise improved motor function, but mortality increased. Two weeks exposure to enriched environment followed by housing the mice in standard cages for 2 weeks, resulted in a loss of the improved motor function. In contrast, 4 weeks exposure to enriched environment led to an improved motor function and to a better maintenance of neurologic recovery. The expression levels of the immediate-early gene nerve growth factor-induced gene A at 2 to 3 weeks of recovery decreased in animals housed in enriched environment, implying this transcription factor in the recovery process. We conclude that housing mice in an enriched environment after experimental stroke improves functional outcome. Also, the presented experimental procedure is useful for further studies of the genomics of functional recovery after experimental stroke.
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Kolbinger, Anja, Roxane Isabelle Kestner, Lara Jencio, Tim J. Schäufele, Rajkumar Vutukuri, Waltraud Pfeilschifter, and Klaus Scholich. "Behind the Wall—Compartment-Specific Neovascularisation during Post-Stroke Recovery in Mice." Cells 11, no. 10 (May 17, 2022): 1659. http://dx.doi.org/10.3390/cells11101659.
Full textAbstract:
Ischemic stroke is a highly prevalent vascular disease leading to oxygen- and glucose deprivation in the brain. In response, ischemia-induced neovascularization occurs, which is supported by circulating CD34+ endothelial progenitor cells. Here, we used the transient middle cerebral artery occlusion (tMCAO) mouse model to characterize the spatio-temporal alterations within the ischemic core from the acute to the chronic phase using multiple-epitope-ligand cartography (MELC) for sequential immunohistochemistry. We found that around 14 days post-stroke, significant angiogenesis occurs in the ischemic core, as determined by the presence of CD31+/CD34+ double-positive endothelial cells. This neovascularization was accompanied by the recruitment of CD4+ T-cells and dendritic cells as well as IBA1+ and IBA1− microglia. Neighborhood analysis identified, besides pericytes only for T-cells and dendritic cells, a statistically significant distribution as direct neighbors of CD31+/CD34+ endothelial cells, suggesting a role for these cells in aiding angiogenesis. This process was distinct from neovascularization of the peri-infarct area as it was separated by a broad astroglial scar. At day 28 post-stroke, the scar had emerged towards the cortical periphery, which seems to give rise to a neuronal regeneration within the peri-infarct area. Meanwhile, the ischemic core has condensed to a highly vascularized subpial region adjacent to the leptomeningeal compartment. In conclusion, in the course of chronic post-stroke regeneration, the astroglial scar serves as a seal between two immunologically active compartments—the peri-infarct area and the ischemic core—which exhibit distinct processes of neovascularization as a central feature of post-stroke tissue remodeling. Based on our findings, we propose that neovascularization of the ischemic core comprises arteriogenesis as well as angiogenesis originating from the leptomenigeal vasculature.
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Liu, Yanfang, Yufeng Li, Jiankun Zang, Tianyuan Zhang, Yaojie Li, Zefeng Tan, Dan Ma, et al. "CircOGDH Is a Penumbra Biomarker and Therapeutic Target in Acute Ischemic Stroke." Circulation Research 130, no. 6 (March 18, 2022): 907–24. http://dx.doi.org/10.1161/circresaha.121.319412.
Full textAbstract:
Background: Acute ischemic stroke (AIS) is a leading cause of disability and mortality worldwide. Prediction of penumbra existence after AIS is crucial for making decision on reperfusion therapy. Yet a fast, inexpensive, simple, and noninvasive predictive biomarker for the poststroke penumbra with clinical translational potential is still lacking. We aim to investigate whether the CircOGDH (circular RNA derived from oxoglutarate dehydrogenase) is a potential biomarker for penumbra in patients with AIS and its role in ischemic neuronal damage. Methods: CircOGDH was screened from penumbra of middle cerebral artery occlusion mice and was assessed in plasma of patients with AIS by quantitative polymerase chain reaction. Magnetic resonance imaging was used to examine the penumbra volumes. CircOGDH interacted with miR-5112 (microRNA-5112) in primary cortical neurons was detected by fluorescence in situ hybridization, RNA immunoprecipitation, and luciferase reporter assay. Adenovirus-mediated CircOGDH knockdown ameliorated neuronal apoptosis induced by COL4A4 (Gallus collagen, type IV, alpha IV) overexpression. Transmission electron microscope, nanoparticle tracking analysis, and Western blot were performed to confirm exosomes. Results: CircOGDH expression was dramatically and selectively upregulated in the penumbra tissue of middle cerebral artery occlusion mice and in the plasma of 45 patients with AIS showing a 54-fold enhancement versus noncerebrovascular disease controls. Partial regression analysis revealed that CircOGDH expression was positively correlated with the size of penumbra in patients with AIS. Sequestering of miR-5112 by CircOGDH enhanced COL4A4 expression to elevate neuron damage. Additionally, knockdown of CircOGDH significantly enhanced neuronal cell viability under ischemic conditions. Furthermore, the expression of CircOGDH in brain tissue was closely related to that in the serum of middle cerebral artery occlusion mice. Finally, we found that CircOGDH was highly expressed in plasma exosomes of patients with AIS compared with those in noncerebrovascular disease individuals. Conclusions: These results demonstrate that CircOGDH is a potential therapeutic target for regulating ischemia neuronal viability, and is enriched in neuron-derived exosomes in the peripheral blood, exhibiting a predictive biomarker of penumbra in patients with AIS.
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Hayakawa, Kazuhide, Takafumi Nakano, Keiichi Irie, Sei Higuchi, Masayuki Fujioka, Kensuke Orito, Katsunori Iwasaki, et al. "Inhibition of Reactive Astrocytes with Fluorocitrate Retards Neurovascular Remodeling and Recovery after Focal Cerebral Ischemia in Mice." Journal of Cerebral Blood Flow & Metabolism 30, no. 4 (December 9, 2009): 871–82. http://dx.doi.org/10.1038/jcbfm.2009.257.
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Glial scarring is traditionally thought to be detrimental after stroke. But emerging studies now suggest that reactive astrocytes may also contribute to neurovascular remodeling. Here, we assessed the effects and mechanisms of metabolic inhibition of reactive astrocytes in a mouse model of stroke recovery. Five days after stroke onset, astrocytes were metabolically inhibited with fluorocitrate (FC, 1 nmol). Markers of reactive astrocytes (glial fibrillary acidic protein (GFAP), HMGB1), markers of neurovascular remodeling (CD31, synaptophysin, PSD95), and behavioral outcomes (neuroscore, rotarod latency) were quantified from 1 to 14 days. As expected, focal cerebral ischemia induced significant neurological deficits in mice. But over the course of 14 days after stroke onset, a steady improvement in neuroscore and rotarod latencies were observed as the mice spontaneously recovered. Reactive astrocytes coexpressing GFAP and HMGB1 increased in peri-infarct cortex from 1 to 14 days after cerebral ischemia in parallel with an increase in the neurovascular remodeling markers CD31, synaptophysin, and PSD95. Compared with stroke-only controls, FC-treated mice demonstrated a significant decrease in HMGB1-positive reactive astrocytes and neurovascular remodeling, as well as a corresponding worsening of behavioral recovery. Our results suggest that reactive astrocytes in peri-infarct cortex may promote neurovascular remodeling, and these glial responses may aid functional recovery after stroke.
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Ting, Shun-Ming, Xiurong Zhao, Guanghua Sun, Lidiya Obertas, Mercedes Ricote, and Jaroslaw Aronowski. "Brain Cleanup as a Potential Target for Poststroke Recovery." Stroke 51, no. 3 (March 2020): 958–66. http://dx.doi.org/10.1161/strokeaha.119.027315.
Full textAbstract:
Background and Purpose— Phagocytic cells, such as microglia and blood-derived macrophages, are a key biological modality responsible for phagocytosis-mediated clearance of damaged, dead, or displaced cells that are compromised during senescence or pathological processes, including after stroke. This process of clearance is essential to eliminate the source of inflammation and to allow for optimal brain repair and functional recovery. Transcription factor, RXR (retinoic-X-receptor) is strongly implicated in phagocytic functions regulation, and as such could represent a novel target for brain recovery after stroke. Methods— Primary cultured microglia and bone marrow macrophages were used for phagocytic study. Mice with deleted RXR-α in myeloid phagocytes (Mac-RXR-α −/− ) were subjected to transient middle cerebral artery occlusion to mimic ischemic stroke and then treated with RXR agonist bexarotene. RNA-sequencing and long-term recovery were evaluated. Results— Using cultured microglia, we demonstrated that the RXR-α promotes the phagocytic functions of microglia toward apoptotic neurons. Using mice with deleted RXR-α in myeloid phagocytes (Mac-RXR-α −/− ), we have shown that despite behaving similarly to the control at early time points (up to 3 days, damage established histologically and behaviorally), these Mac-RXR-α −/− mice demonstrated worsened late functional recovery and developed brain atrophy that was larger in size than that seen in control mice. The RXR-α deficiency was associated with reduced expression of genes known to be under control of the prominent transcriptional RXR partner, PPAR (peroxisome proliferator-activated receptor)-γ, as well as genes encoding for scavenger receptors and genes that signify microglia/macrophages polarization to a reparative phenotype. Finally, we demonstrated that the RXR agonist, bexarotene, administered as late as 1 day after middle cerebral artery occlusion, improved neurological recovery, and reduced the atrophy volume as assessed 28 days after stroke. Bexarotene did not improve outcome in Mac-RXR-α −/− mice. Conclusions— Altogether, these data suggest that phagocytic cells control poststroke recovery and that RXR in these cells represents an attractive target with exceptionally long therapeutic window.
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Bice, Annie R., Qingli Xiao, Justin Kong, Ping Yan, Zachary Pollack Rosenthal, Andrew W. Kraft, Karen P. Smith, et al. "Homotopic contralesional excitation suppresses spontaneous circuit repair and global network reconnections following ischemic stroke." eLife 11 (June 20, 2022). http://dx.doi.org/10.7554/elife.68852.
Full textAbstract:
Understanding circuit-level manipulations that affect the brain's capacity for plasticity will inform the design of targeted interventions that enhance recovery after stroke. Following stroke, increased contralesional activity (e.g. use of the unaffected limb) can negatively influence recovery, but it is unknown which specific neural connections exert this influence, and to what extent increased contralesional activity affects systems- and molecular-level biomarkers of recovery. Here, we combine optogenetic photostimulation with optical intrinsic signal imaging (OISI) to examine how contralesional excitatory activity affects cortical remodeling after stroke in mice. Following photothrombosis of left primary somatosensory forepaw (S1FP) cortex, mice either recovered spontaneously or received chronic optogenetic excitation of right S1FP over the course of 4 weeks. Contralesional excitation suppressed perilesional S1FP remapping and was associated with abnormal patterns of stimulus-evoked activity in the unaffected limb. This maneuver also prevented the restoration of resting-state functional connectivity (RSFC) within the S1FP network, RSFC in several networks functionally-distinct from somatomotor regions, and resulted in persistent limb-use asymmetry. In stimulated mice, perilesional tissue exhibited transcriptional changes in several genes relevant for recovery. Our results suggest that contralesional excitation impedes local and global circuit reconnection through suppression of cortical activity and several neuroplasticity-related genes after stroke, and highlight the importance of site selection for therapeutic intervention after focal ischemia.