Creatine benzyl ester is effective for prevention and treatment of neurological and cognitive disorders caused by focal cerebral ischemia in rats

2021 ◽  
pp. 35-41
Author(s):  
В.О. Муровец ◽  
М.В. Ленцман
Keyword(s):  
Cognitive Impairment ◽  
Cerebral Ischemia ◽  
Neurological Disorders ◽  
Focal Cerebral Ischemia ◽  
Cognitive Disorders ◽  
Benzyl Ester ◽  
Left Middle Cerebral Artery ◽  
Synthetic Compound ◽  
Chronic Occlusion ◽  
Prevention And Treatment

Введение. Ишемический инсульт головного мозга является одной из главных причин преждевременных смертей во всем мире, вызванные им когнитивные и функциональные нарушения ведут к инвалидизации. Для клинического использования в настоящее время одобрено лишь одно средство - рекомбинантный активатор плазминогена, который обеспечивает восстановление (реканализацию) мозгового кровотока. Средства эффективной нейропротекции, обеспечивающие непосредственную защиту нейронов от ишемии (предотвращение апоптоза, сохранение функциональной активности), несмотря на огромное число исследований, по-прежнему не найдены. Поиск новых подходов к профилактике и лечению острых нарушений мозгового кровообращения по-прежнему остается одной из наиболее актуальных проблем современной медицины. Цель исследования - изучение влияния бензилового эфира креатина, нового синтетического соединения, обладающего способностью проникать через гематоэнцефалический барьер и осуществлять нейропротекторное действие на неврологические и когнитивные нарушения, вызванные фокальной ишемией головного мозга у крыс линии Спрэг-Доули. Методика. Фокальную ишемию головного мозга (ФИМ) индуцировали путем хронической окклюзии левой средней мозговой артерии (СМА) в соответствии с модификацией методики A. Tamura и соавт., 1981. Использовали комбинированный наркоз: Золетил/Домитор (внутрибрюшинно (в/б) по 50 мг/кг и 0.2 мг/кг, соответственно), температуру тела поддерживали постоянной на уровне 38±0.5 oC. Окклюзию СМА производили путем биполярной высокочастотной электрокоагуляции (аппарат ЭХВЧ-25-11-С, «Медия», Россия) наиболее проксимального участка артерии, начиная с 0.5 мм от места ее отхождения от Виллизиева круга и на протяжении 2-3 мм. Процедура имитации ишемии (ложная операция) была аналогична вышеизложенной, но без электрокоагуляции СМА. Оценку степени неврологических нарушений проводили с использованием неврологической шкалы Гарсии и модифицированной шкалы тяжести неврологических нарушений (ОТНН) последовательно за 1 сут до и через 1, 3 и 7 сут после моделирования ФИМ. Для выявления когнитивных нарушений использовали водный лабиринт Морриса. Стандартный тест исследования процессов обучения и памяти применяли в версии для оценки пространственной референтной памяти, заключающейся в поиске животным скрытой под водой платформы при ориентации только по приметам окружающей обстановки. Бензиловый эфир креатина вводили внутрибрюшинно трижды - за 3, 2 и 1 ч до фокальной ишемии при профилактическом применении, либо через 1, 2 и 3 ч после моделирования ишемии при лечебном применении. Результаты. Получены приоритетные данные о том, что бензиловый эфир креатина при профилактическом введении эффективно предупреждает развитие неврологических нарушений и ослабляет когнитивные нарушения после фокальной ишемии мозга; при лечебном применении препарат ослабляет тяжесть неврологических нарушений и снижает выраженность когнитивных расстройств. Заключение. Результаты исследования позволяют рекомендовать данное производное креатина (после оценки возможной токсичности) для проведения первой фазы клинических испытаний в качестве препарата противоишемического действия. Background. Ischemic stroke is one of the main causes for premature death worldwide. Cognitive and functional disorders induced by stroke result in disability. Currently, only one agent has been approved for the clinical use, recombinant plasminogen activator, which provides recovery (recanalization) of cerebral blood flow. Despite numerous studies, an effective treatment to protect directly neurons from ischemia (preventing apoptosis, maintaining functional activity) has not been found so far. Thus, search for new approaches to prevention and treatment of acute cerebrovascular accidents remains one of the most pressing challenges of modern medicine. The aim of this work was to study the effect of creatine benzyl ester, a new synthetic compound capable for penetrating the blood-brain barrier to provide neuroprotection, on neurological and cognitive disorders induced by focal cerebral ischemia in Sprague-Dawley rats. Methods. Focal cerebral ischemia was induced by chronic occlusion of the left middle cerebral artery (MCA) by a A. Tamura et al. (1981) modified method. Combined intraperitoneal (i.p.) anesthesia with Zoletil/Domitor (50 mg/kg and 0.2 mg/kg, respectively) was used. Body temperature was maintained at 38±0.5 oC. MCA occlusion was performed by bipolar high-frequency electrocoagulation (EKVCh-25-11-C, Media, Russia) of the most proximal part of the artery, from 0.5 mm from the place where it originates from the circle of Willis and over 2-3 mm. The sham ischemia procedure was similar to that described above but without MCA electrocoagulation. Severity of neurological disorders was assessed with the Garcia neurological scale and a modified scale for severity of neurological disorders (OTTN) one day before and at 1, 3, and 7 days following ischemia. Cognitive impairment was assessed with the Morris water maze, a standard test for learning and memory. This test was used in a version for studying spatial reference memory, which consists of finding a platform hidden under the water by the animal guided only by surrounding marks. Creatine benzyl ester was injected i.p. three times, 3, 2 and 1 h before focal ischemia for prevention or 1, 2 and 3 h after ischemia for treatment. Results. The study produced priority data showing that preventive administration of creatine benzyl ester effectively abolished the development of neurological disorders and alleviated the cognitive impairment after focal cerebral ischemia whereas the therapeutic treatment restricted the severity of neurological and cognitive disorders. Conclusion. The results of the study supported recommendation of this creatine derivative (after assessing potential toxicity) for the first phase of clinical trials as an anti-ischemic drug.

FEATURES OF COGNITIVE IMPAIRMENT DEPENDING ON THE STAGE OF CHRONIC CEREBRAL ISCHEMIA

2021 ◽  
Vol 2 (1) ◽  
pp. 56-61
Author(s):  
Munis Dilshod qizi Fayzieva ◽  
◽  
Durdona Djurabaevna Usmanova
Keyword(s):  
Adverse Effect ◽  
Cognitive Impairment ◽  
Cerebral Ischemia ◽  
Neurological Disorders ◽  
Cognitive Disorders ◽  
Chronic Cerebral Ischemia ◽  
Common Cause ◽  
Local Factors ◽  
Atherosclerotic Stenosis ◽  
Stenosis And Occlusion

The article presents the results of the analysis of literature sources on chronic cerebral ischemia, etiology and pathogenetic mechanisms of the development of cognitive impairment. In the pathogenesis of chronic cerebral ischemia, systemic and local factors are important, leading to disorders of cerebral hemodynamics, the most adverse effect is exerted by their combination. The most common cause of local disorders of cerebral blood flow is atherosclerotic stenosis and occlusion of intracerebral and extracranial vesselsthat perform transport and distribution functions.Keywords: chronic cerebral ischemia, cognitive disorders, neurological disorders

Nonhyperemic blood flow restoration and brain edema in experimental focal cerebral ischemia

1989 ◽  
Vol 70 (1) ◽  
pp. 73-80 ◽  
Author(s):  
Toshihiko Kuroiwa ◽  
Makoto Shibutani ◽  
Riki Okeda
Keyword(s):  
Blood Flow ◽  
Cerebral Ischemia ◽  
Brain Edema ◽  
Focal Cerebral Ischemia ◽  
Reactive Hyperemia ◽  
Diffusion Method ◽  
Left Middle Cerebral Artery ◽  
Content Type ◽  
Bbb Opening ◽  
Fine Print

✓ The effect of suppression of postischemic reactive hyperemia on the blood-brain barrier (BBB) and ischemic brain edema after temporary focal cerebral ischemia was studied in cats under ketamine and alpha-chloralose anesthesia. Regional cerebral blood flow (rCBF) was measured by a thermal diffusion method and a hydrogen clearance method. The animals were separated into three groups. In Group A, the left middle cerebral artery (MCA) was occluded for 6 hours. In Group B, the MCA was occluded for 3 hours and then reperfused for 3 hours; postischemic hyperemia was suppressed to the preischemic level by regulating the degree of MCA constriction. In Group C, the MCA was occluded for 3 hours and reperfused for 3 hours without suppressing the postischemic reactive hyperemia. The brain was removed and cut coronally at the site of rCBF measurement. The degree of ischemic edema was assessed by gravimetry in samples taken from the coronal section and correlated with the degree of BBB disruption at the corresponding sites, evaluated by densitometric determination of Evans blue discoloration. The findings showed that 1) ischemic edema was significantly exacerbated by postischemic hyperemia during reperfusion in parallel with the degree of BBB opening to serum proteins, and 2) suppression of postischemic hyperemia significantly reduced the exacerbation of ischemic edema and BBB opening. These findings indicate that blood flow may be restored without significant exacerbation of postischemic edema by the suppression of postischemic hyperemia in focal cerebral ischemia.

SMI-32 — a novel axonal injury marker for investigation of ischemic brain pathology

2021 ◽  
Vol 20 (4) ◽  
pp. 63-68
Author(s):  
Daria L. Tsyba ◽  
Olga V. Kirik ◽  
Dmitrii E. Korzhevskii
Keyword(s):  
Cerebral Ischemia ◽  
Heavy Chain ◽  
Neuronal Damage ◽  
Focal Cerebral Ischemia ◽  
Axonal Injury ◽  
Experimental Models ◽  
Nerve Fibers ◽  
Left Middle Cerebral Artery ◽  
Social Significance ◽  
Neurofilament Proteins

The relevance of this work is determined by the high prevalence and social significance of cerebrovascular diseases and the need to develop effective methods for verifying neuronal damage due to cerebral ischemia in experimental models. The aim of this study was to assess the possibility of immunohistochemical revealing of neurofilaments to detect axonal injury in cerebral ischemia models. Materials and methods. A model of transient focal cerebral ischemia by the left middle cerebral artery occlusion was reproduced in male Wistar, SHR and WKY rats. Axonal injury was assessed by immunohistochemical reactions for neurofilament proteins using SMI-32 and 2F11 antibodies. Results. In cerebral ischemia, damage to nerve fibers occurs, manifested by thickening of axons, their varicose expansion and segmental accumulation of neurofilament proteins. These changes are more noticeable with an immunohistochemical reaction to the SMI-32 marker of neurofilament heavy chain. Conclusions. The use of antibodies to the non-phosphorylated neurofilament heavy chain makes it easy to identify degenerating nerve fibers and can be recommended as an alternative method for detecting axonal injury.

scholarly journals Modulation by Nitric Oxide of Cerebral Neutrophil Accumulation after Transient Focal Ischemia in Rats

2000 ◽  
Vol 20 (5) ◽  
pp. 812-819 ◽  
Author(s):  
Sophie Batteur-Parmentier ◽  
Isabelle Margaill ◽  
Michel Plotkine
Keyword(s):  
Nitric Oxide ◽  
Cerebral Ischemia ◽  
Focal Cerebral Ischemia ◽  
Infarct Volume ◽  
Neutrophil Infiltration ◽  
Focal Ischemia ◽  
Left Middle Cerebral Artery ◽  
No Production ◽  
Myeloperoxidase Activity ◽  
Transient Focal Ischemia

A beneficial role of nitric oxide (NO) after cerebral ischemia has been previously attributed to its vascular effects. Recent data indicate a regulatory role for NO in initial leukocyte-endothelial interactions in the cerebral microcirculation under basal and ischemic conditions. In this study, the authors tested the hypothesis that endogenous NO production during and/or after transient focal cerebral ischemia can also be neuroprotective by limiting the process of neutrophil infiltration and its deleterious consequences. Male Sprague-Dawley rats were subjected to 2 hours occlusion of the left middle cerebral artery and the left common carotid artery. The effect of NG-nitro-L-arginine methyl ester (L-NAME) (10 mg/kg, intraperitoneally), an NO synthase inhibitor, was examined at 48 hours after ischemia on both infarct size and myeloperoxidase activity, an index of neutrophil infiltration. L-NAME given 5 minutes after the onset of ischemia increased the cortical infarct volume by 34% and increased cortical myeloperoxidase activity by 60%, whereas administration of L-NAME at 1, 7, and 22 hours of reperfusion had no effect. Such exacerbations of infarction and myeloperoxidase activity produced when L-NAME was given 5 minutes after the onset of ischemia were not observed in rats rendered neutropenic by vinblastine. These results suggest that after transient focal ischemia, early NO production exerts a neuroprotective effect by modulating neutrophil infiltration.

scholarly journals Short Therapeutic Window for MK-801 in Transient Focal Cerebral Ischemia in Normotensive Rats

1996 ◽  
Vol 16 (1) ◽  
pp. 107-113 ◽  
Author(s):  
I. Margaill ◽  
S. Parmentier ◽  
J. Callebert ◽  
M. Allix ◽  
R. G. Boulu ◽  
...  
Keyword(s):  
Cerebral Ischemia ◽  
Nmda Receptors ◽  
Focal Cerebral Ischemia ◽  
Infarct Volume ◽  
Neuroprotective Activity ◽  
Therapeutic Window ◽  
Left Middle Cerebral Artery ◽  
Mk 801 ◽  
Transient Focal Cerebral Ischemia

The present study investigates the role of N-methyl-D-aspartate (NMDA) receptors in a model of transient focal cerebral ischemia in normotensive rats. The left middle cerebral artery and both common carotid arteries were occluded for 60 min. Preliminary studies indicated that this gave reproducible infarctions of the cortex and striatum. These infarctions were the result of severe ischemia followed by complete reperfusion after clamp removal, as showed by striatal tissue Po2 monitoring. Microdialysis indicated that glutamate concentration increased immediately after occlusion and returned to the baseline value 40 min after clamp removal. MK-801 (1 mg kg−1 i.v.), an antagonist of the NMDA glutamatergic receptor, reduced the cortical infarct volume by 29% (p < 0.001) and the striatal infarct volume by 14% (p < 0.05) when given just prior to ischemia, but had no neuroprotective activity when given 30 min after the onset of ischemia. This short therapeutic window for MK-801 suggests that NMDA receptors play only a transient role in reversible focal ischemia in rats.

scholarly journals Chronic treatment of 4-phenylbutyric acid ameliorates cognitive impairment after focal cerebral ischemia/ reperfusion injury in rats

2021 ◽  
Vol 64 ◽  
pp. 188-194
Author(s):  
Kakarla Ramakrishna ◽  
Krishnamoorthy Srinivasan ◽  
Shyam Sunder Sharma
Keyword(s):  
Cognitive Impairment ◽  
Cerebral Ischemia ◽  
Learning And Memory ◽  
Focal Cerebral Ischemia ◽  
Ischemia Reperfusion ◽  
Motor Deficits ◽  
Avoidance Task ◽  
Neurological Score ◽  
Y Maze ◽  
Phenylbutyric Acid

Objectives: Stroke, apart from causing physical disabilities, it also often leads to cognitive impairment in patients. At present, there is no effective drug available for the treatment of post-stroke cognitive impairment. The present study was undertaken to evaluate the ameliorative effect of 4-Phenylbutyric acid (PBA) against cognitive and memory deficits due to focal cerebral ischemia/reperfusion (I/R) in rats. Materials and Methods: Focal cerebral I/R injury was achieved by the middle cerebral artery occlusion (MCAO) method. PBA (100 and 300 mg/kg, i.p.) was administered once daily for 2 weeks. The neurological score was counted to evaluate the severity of neurological motor deficits. The cognitive functions, including learning and memory, were assessed using various paradigms such as Y-maze, passive avoidance task and Morris water maze. Results: The chronic treatment of PBA (100 and 300 mg/kg, i.p.) dose-dependently improved the neurological motor deficits as shown by significant decrease in neurological score in MCAO-treated rats. Besides, PBA (100 and 300 mg/kg, i.p.) treatment markedly improved working memory as shown by significant increase in the relative percentage alternations compared to untreated control MCAO rats in Y-maze. PBA also significantly decreased the transfer latency in the acquisition trial and increased in probe trial in passive avoidance task suggesting an improvement in learning and memory in MCAO rats. There was also a significant improvement in spatial learning and memory, as evidenced by the reduced escape latency in acquisition trial and the increased number of entries into the platform zone, time spent in the platform quadrant and track plot in probe trial PBA-treated MCAO rats during Morris water maze task. Conclusion: This study, thus, demonstrates the potential of PBA in ameliorating cognitive dysfunctions in focal cerebral ischemia. Since PBA is already available for the treatment of urea cycle disorders, it may also be investigated for repurposing its use in the treatment of post-stroke cognitive impairment.

scholarly journals Acute Improvement in Histological Outcome by MK-801 following Focal Cerebral Ischemia and Reperfusion in the Cat Independent of Blood Flow Changes

1992 ◽  
Vol 12 (3) ◽  
pp. 390-399 ◽  
Author(s):  
Laszlo Dezsi ◽  
Joel H. Greenberg ◽  
Janos Hamar ◽  
John Sladky ◽  
Andrea Karp ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Blood Flow ◽  
Cerebral Ischemia ◽  
Focal Cerebral Ischemia ◽  
Left Middle Cerebral Artery ◽  
Ischemia And Reperfusion ◽  
Partial Recovery ◽  
Mk 801 ◽  
Cerebral Ischemia And Reperfusion ◽  
Flow Changes

The present study reports on the acute effects of MK-801 on the histopathological outcome and blood flow changes during focal cerebral ischemia and reperfusion. In addition, acute changes in the EEG and blood pressure are also reported. In 16 halothane-anesthetized cats, the left middle cerebral artery (MCA) was occluded for 2 h followed by 4 h of reperfusion. Thirty minutes after the onset of ischemia, eight animals were treated with 1 mg/kg of MK-801, while eight animals received saline. Blood flow from the peripheral MCA territory was measured with H2 clearance. There was a comparable reduction in blood flow (down to 20% of control) in the ischemic gyri of the two groups followed by a partial recovery after recirculation. There was a similar decrease in the EEG amplitude over the ischemic central MCA territory in the treated and the untreated group. Treatment with MK-801 induced a burst suppression in the EEG and a transient drop (11.4 ± 6.5 mm Hg) in the mean arterial pressure. The volume of early ischemic damage decreased by one-third in the MK-801-treated group compared to the untreated one, both in the total hemisphere (from 29 ± 10 to 20 ± 5%) and in the hemispheric cortex (range 36 ± 8 to 24 ± 13%). A major fraction of this improvement was localized to the middle and posterior parietal (mainly perifocal) regions of the MCA territory. These results show that in our model, MK-801 improves histopathological outcome despite the lack of apparent effect on the cortical blood flow, and an adverse effect on the systemic blood pressure. This is the first report that describes data on a reproducible model of reperfusion after temporary occlusion of the MCA in a cat, extending the findings of the Glasgow group, who observed similar neuroprotection in models of permanent MCA occlusion.

scholarly journals Na+-K+-Cl− Cotransporter in Rat Focal Cerebral Ischemia

2001 ◽  
Vol 21 (6) ◽  
pp. 711-721 ◽  
Author(s):  
Yiping Yan ◽  
Robert J. Dempsey ◽  
Dandan Sun
Keyword(s):  
Cerebral Ischemia ◽  
Neuronal Damage ◽  
Focal Cerebral Ischemia ◽  
Treated Group ◽  
Immunocytochemical Staining ◽  
Extracellular Potassium ◽  
Left Middle Cerebral Artery ◽  
Regulation Of Expression ◽  
Microdialysis Probe ◽  
Cerebral Ischemic

In cultured neurons, the authors previously demonstrated that the Na+-K+-Cl− cotransporter is significantly stimulated by elevated extracellular potassium and glutamate, which are important factors in cerebral ischemic damage. These findings led the authors to hypothesize that stimulation of the cotransporter after ischemia might result in Na+, K+, and Cl− influx, and might contribute to neuron damage. In the current study, the authors investigated such a role of the Na+-K+-Cl− cotransporter in focal cerebral ischemia. Cerebral ischemia was induced by 2-hour occlusion of the left middle cerebral artery (MCA) and 24-hour reperfusion in male spontaneously hypertensive rats (SHRs). Immunocytochemical staining and immunoblotting revealed an up-regulation of expression of the cotransporter protein in neurons in cortex at 24 hours of reperfusion. Artificial cerebral spinal fluid (aCSF) or 100 μmol/L bumetanide (a cotransporter inhibitor) in aCSF were continuously microdialyzed through a microdialysis probe into left cortices throughout 2-hour MCA occlusion and 24-hour reperfusion. Compared with the aCSF-treated group, infarction volume was significantly reduced in the bumetanide-treated group (25%, P < 0.05). In addition, brain water content in the bumetanide-treated brains was decreased by 70% ( P < 0.05). These results strongly suggest that the Na+-K+-Cl− cotransporter may play an important role in cerebral ischemic neuronal damage.

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