Department of Pharmacology, PSG College of Pharmacy, Coimbatore, 641004, Tamilnadu, India.
Department of Pharmacology, Girijananda Chowdhury Institute of Pharmaceutical Science, Girijananda Chowdhury University, Dekargaon, Tezpur, 784501, Assam, India.
Naunyn Schmiedebergs Arch Pharmacol. 2024 Jan;397(1):479-496. doi: 10.1007/s00210-023-02616-0. Epub 2023 Jul 20.
Cerebral ischemia is one of the leading causes of death and disability worldwide. The only FDA-approved treatment is recanalization with systemic tissue plasminogen activators like alteplase, although reperfusion caused by recanalization can result in neuroinflammation, which can cause brain cell apoptosis. Therefore, after an ischemic/reperfusion injury, interventions are needed to minimize the neuroinflammatory cascade. In the present study, piceatannol (PCT) was studied for its neuroprotective efficacy in a rat model of global ischemic injury by attenuating c-Jun N-terminal kinase 3 (JNK3) downstream signaling. PCT is a resveratrol analog and a polyphenolic stilbenoid naturally occurring in passion fruit and grapes. The neuroprotective efficacy of PCT (1, 5, 10 mg/kg) in ischemic conditions was assessed through pre- and post-treatment. Cerebral blood flow (CBF) and tests for functional recovery were assessed. Protein and gene expression were done for JNK3 and other inflammatory markers. A docking study was performed to identify the amino acid interaction. The results showed that PCT improved motor and memory function as measured by a functional recovery test believed to be due to an increase in cerebral blood flow. Also, the caspase signaling which promotes apoptosis was found to be down-regulated; however, nitric oxide synthase expression was up-regulated, which could explain the enhanced cerebral blood flow (CBF). According to our findings, PCT impeded c-Jun N-terminal kinase 3 (JNK3) signaling by suppressing phosphorylation and disrupting the mitochondrial apoptotic pathway, which resulted in the neuroprotective effect. Molecular docking analysis was performed to investigate the atomic-level interaction of JNK3 and PCT, which reveals that Met149, Leu206, and Lys93 amino acid residues are critical for the interaction of PCT and JNK3. According to our current research, JNK3 downstream signaling and the mitochondrial apoptosis pathway are both inhibited by PCT, which results in neuroprotection under conditions of global brain ischemia. Piceatannol attenuated JNK3 phosphorylation during the ischemic condition and prevented neuronal apoptosis.
脑缺血是全球范围内导致死亡和残疾的主要原因之一。唯一获得 FDA 批准的治疗方法是使用全身性组织纤溶酶原激活剂（如阿替普酶）进行再通，但再通引起的再灌注会导致神经炎症，从而导致脑细胞凋亡。因此，在缺血/再灌注损伤后，需要进行干预以最大限度地减少神经炎症级联反应。在本研究中，通过减弱 c-Jun N 末端激酶 3（JNK3）下游信号，研究了白藜芦醇类似物白皮杉醇（PCT）在大鼠全脑缺血损伤模型中的神经保护作用。PCT 是一种白藜芦醇类似物和多酚类芪类物质，天然存在于西番莲和葡萄中。通过预处理和后处理评估了 PCT（1、5、10mg/kg）在缺血条件下的神经保护作用。评估了脑血流量（CBF）和功能恢复测试。进行了 JNK3 和其他炎症标志物的蛋白和基因表达。进行了对接研究以鉴定氨基酸相互作用。结果表明，PCT 通过增加脑血流量改善了运动和记忆功能，这被认为是由于功能恢复测试的改善。此外，还发现促进细胞凋亡的半胱天冬酶信号被下调；然而，一氧化氮合酶的表达被上调，这可以解释增强的脑血流量（CBF）。根据我们的发现，PCT 通过抑制磷酸化和破坏线粒体凋亡途径来阻止 c-Jun N 末端激酶 3（JNK3）信号，从而产生神经保护作用。进行了分子对接分析以研究 JNK3 和 PCT 之间的原子水平相互作用，结果表明 Met149、Leu206 和 Lys93 氨基酸残基对于 PCT 和 JNK3 的相互作用至关重要。根据我们目前的研究，PCT 抑制了 JNK3 下游信号和线粒体凋亡途径，从而在全脑缺血情况下实现神经保护。PCT 在缺血条件下减弱了 JNK3 的磷酸化作用，并防止了神经元凋亡。
