Therapeutic potential of the novel hybrid molecule JM-20 against focal cortical ischemia in rats
نویسندگان
چکیده
Resumen Context: Despite the great mortality and morbidity of stroke, treatment options remain limited. We previously showed that JM-20, a novel synthetic molecule, possessed a strong neuroprotective effect in rats subjected to transient middle cerebral artery occlusion. However, to verify the robustness of the pre-clinical neuroprotective effects of JM-20 to get good prognosis in the translation to the clinic, it is necessary to use other experimental models of brain ischemia. Aims: To evaluate the neuroprotective effects of JM-20 following the onset of permanent focal cerebral ischemia induced in rats by thermocoagulation of blood into pial blood vessels of cerebral cortices. Methods: Ischemic lesion was induced by thermocoagulation of blood into pial blood vessels of primary motor and somatosensory cortices. Behavioral performance was evaluated by the cylinder testing for a period of 2, 3 and 7 days after surgery, and was followed by histopathological study in brain cortex stained with hematoxylineosin. Results: Ischemic injury resulted in impaired function of the forelimb evidenced by high asymmetry punctuation, and caused histopathological alterations indicative of tissue damage at cerebral cortex. JM-20 treatment (4 and 8 mg/kg) significantly decreased asymmetry scores and histological alterations with a marked preservation of cortical neurons. Conclusions: The effects of permanent brain ischemia were strongly attenuated by JM-20 administration, which expands and improves the current preclinical data of JM-20 as neuroprotector against cerebral ischemia, and strongly support the examination of its translation to the clinic to treat acute ischemic stroke. Contexto: A pesar de la enorme mortalidad y morbilidad del infarto cerebral, las opciones terapéuticas son limitadas. Recientemente se ha demostrado que JM-20, nueva molécula sintética, ejerce efecto neuroprotector en ratas sometidas a una oclusión transitoria de la arteria cerebral media. Sin embargo, se hace necesario utilizar otros modelos experimentales de isquemia cerebral. Objetivos: Evaluar el efecto neuroprotector del JM-20 luego del comienzo de una isquemia cerebral focal y permanente en ratas, inducida por termocoagulación de la sangre en los vasos piales de la corteza cerebral. Métodos: La lesión isquémica se indujo por termocoagulación de la sangre en los vasos piales de la corteza primaria motora y somato sensorial. El desempeño comportamental se evaluó por medio de la prueba del cilindro a los 2, 3 y 7 días después de la cirugía. Posteriormente se realizaron estudios histopatológicos en corteza cerebral por medio de la tinción con hematoxilina-eosina. Resultados: El daño isquémico resultó en un impedimento funcional de las extremidades anteriores de las ratas evidenciado por una elevada asimetría y originó alteraciones histopatológicas indicativas de daño en la corteza cerebral. El tratamiento con JM-20 (4 y 8 mg/kg) disminuyó significativamente los porcientos de asimetría y las alteraciones histopatológicas con una marcada preservación de las neuronas corticales. Conclusiones: Los efectos de la isquemia cerebral permanente fueron fuertemente atenuados por la administración del JM-20, lo que enriquece y mejora su data experimental pre-clínica como neuroprotector contra la isquemia cerebral y apoya la consideración de su traslado a la clínica para tratar el infarto cerebral.
منابع مشابه
L-NAME and 7-Nitroindazole Reduces Brain Injuries in Transient Focal Cerebral Ischemia in Rat
Background: The role of nitric oxide (NO) of endothelial or neuronal origins in cerebral ischemia and reperfusion injuries are far from being settled, extending from being important to not having any role at all. Objective: To investigate the role of NO of endothelial and neuronal origins in ischemia/reperfusion injuries in focal cerebral ischemia, L-NAME, a non selective NO synthase inhibitor...
متن کاملبررسی اثرات دیمتیل سولفوکساید بر ضایعات و اختلالات نورولوژیک در ایسکمی مغزی موضعی موقتی در موش صحرایی
Background: Dimethyl sulfoxide (DMSO) has been used as a solvent for many drugs in ischemic experiments. DMSO has many biological benefits, including antioxidant, anti-inflammatory, platelet aggregation inhibiting and cell membrane stabilizing effects. Moreover, some experimental studies report that DMSO has a neurprotective effect in permanent focal cerebral ischemia. Despite the effect of DMS...
متن کاملComparison effect of pentobarbital sodium with chloral hydrate anesthesia on post-ischemic damage in an experimental model of focal cerebral ischemia
Introduction: Anesthetic agents, blood pressure, arterial pH and blood gases have found to influence on the pathophysiology of experimental stroke. Despite, there are very few comparative studies about effects of anesthetic agents in animal model of cerebral ischemia. Therefore, in this study, we investigated the effects of chloral hydrate and pentobarbital anesthesia, as comparative study, on...
متن کاملPre-Ischemic Treatment of Pentoxifylline Reduces Infarct Volumes in Transient Focal Cerebral Ischemia in the Rat
Background: Pentoxifylline (PTX) is used in human for intermittent claudication and cerebral vascular disorders including cerebrovascular dementia. It also inhibits the synthesis of tumor necrosis factor-α (TNF-α), which is believed to be neurotoxic in animal models of cerebral ischemia. The objective of this study was to examine the role of PTX on ischemia/reperfusion injures in rat model of t...
متن کاملInhibition of Angiotensin-Converting Enzyme Reduces Cerebral Infarction Size in Experimental-Induced Focal Cerebral Ischemia in the Rat
Background: The role of Renin Angiotensin System (RAS) in ischemic/reperfusion (I/R) injuries is not fully elucidated. Furthermore, it is not clear whether inhibition of RAS by Angiotensin-Converting Enzyme (ACE) inhibitors has beneficial effects in terms of protecting the brain from I/R injuries. In this study enalapril is used as an ACE inhibitor to evaluate the role of RAS in I/R injuries in...
متن کامل