Wasan Himika, Singh Devendra, Joshi Balu, Sharma Uma, Dinda A K, Reeta K H
Department of Pharmacology, All India Institute of Medical Sciences, New Delhi, India.
Department of NMR, All India Institute of Medical Sciences, New Delhi, India.
Mol Neurobiol. 2021 Dec;58(12):6121-6135. doi: 10.1007/s12035-021-02523-6. Epub 2021 Aug 28.
Exploring and repurposing a drug have become a lower risk alternative. Safinamide, approved for Parkinson's disease, has shown neuroprotection in various animal models of neurological disorders. The present study aimed to explore the potential of safinamide in cerebral ischemia/reperfusion (I/R) in rats. Sprague-Dawley rats were used in middle cerebral artery occlusion model of stroke. The effective dose of safinamide was selected based on the results of neurobehavioral parameters and reduction in infarct size assessed 24 h post-reperfusion. For sub-acute study, the treatment with effective dose was extended for 3 days and effects on neurobehavioral parameters, infarct size (TTC staining and MRI), oxidative stress parameters (MDA, GSH, SOD, NOX-2), inflammatory cytokines (TNF-α, IL-1β, IL-10), apoptosis (Bax, Bcl-2, cleaved caspase-3 expression, and TUNEL staining), and autophagy (pAMPK, Beclin-1, LC3-II expression) were studied. The results of dose selection study showed significant reduction (p < 0.05) in infarct size and improvement in neurobehavioral parameters with safinamide (80 mg/kg). In sub-acute study, safinamide showed significant (p < 0.05) improvement in motor coordination and infarct size reduction. Additionally, safinamide treatment significantly normalized altered redox homeostasis and inflammatory cytokine levels. However, no change was observed in expression of NOX-2 in I/R or safinamide treatment group when compared with sham. I/R induced deranged expression of apoptotic markers and increased TUNEL positive cells in cortex were significantly normalized with safinamide treatment. Further, safinamide significantly (p < 0.05) induced the expressions of autophagic proteins (Beclin-1 and LC3-II) in cortex. Overall, the results demonstrated neuroprotective potential of safinamide via anti-oxidant, anti-inflammatory, anti-apoptotic, and autophagy inducing properties. Thus, safinamide can be explored for repurposing in ischemic stroke after further exploration.
探索和重新利用一种药物已成为一种风险较低的选择。已获批准用于治疗帕金森病的沙芬酰胺，在多种神经疾病动物模型中均显示出神经保护作用。本研究旨在探讨沙芬酰胺对大鼠脑缺血/再灌注（I/R）损伤的潜在作用。在大脑中动脉闭塞性脑卒中模型中使用Sprague-Dawley大鼠。根据再灌注24小时后评估的神经行为参数结果和梗死灶大小的减小情况，选择沙芬酰胺的有效剂量。对于亚急性研究，将有效剂量的治疗延长3天，并研究其对神经行为参数、梗死灶大小（TTC染色和MRI）、氧化应激参数（丙二醛、谷胱甘肽、超氧化物歧化酶、NOX-2）、炎性细胞因子（肿瘤坏死因子-α、白细胞介素-1β、白细胞介素-10）、细胞凋亡（Bax、Bcl-2、裂解的半胱天冬酶-3表达以及TUNEL染色）和自噬（磷酸化腺苷酸活化蛋白激酶、Beclin-1、LC3-II表达）的影响。剂量选择研究结果显示，沙芬酰胺（80mg/kg）可使梗死灶大小显著减小（p<0.05），并改善神经行为参数。在亚急性研究中，沙芬酰胺显著改善（p<0.05）运动协调性并减小梗死灶大小。此外，沙芬酰胺治疗可使氧化还原稳态和炎性细胞因子水平的改变显著恢复正常。然而，与假手术组相比，I/R组或沙芬酰胺治疗组中NOX-2的表达未观察到变化。沙芬酰胺治疗可使I/R诱导的凋亡标志物表达紊乱以及皮质中TUNEL阳性细胞增加的情况显著恢复正常。此外，沙芬酰胺显著（p<0.05）诱导皮质中自噬蛋白（Beclin-1和LC3-II）的表达。总体而言，结果表明沙芬酰胺具有通过抗氧化、抗炎、抗凋亡和诱导自噬的特性发挥神经保护的潜力。因此，经过进一步探索后，沙芬酰胺可用于探索其在缺血性脑卒中治疗中的新用途。
