The Cannabinoid Receptor Agonist WIN55,212-2 Ameliorates Hippocampal Neuronal Damage After Chronic Cerebral Hypoperfusion Possibly Through Inhibiting Oxidative Stress and ASK1-p38 Signaling
The Cannabinoid Receptor Agonist WIN55,212-2 Ameliorates Hippocampal Neuronal Damage After Chronic Cerebral Hypoperfusion Possibly Through Inhibiting Oxidative Stress and ASK1-p38 Signaling
复制标题
大麻素受体激动剂 WIN55,212-2 可能通过抑制氧化应激和 ASK1-p38 信号传导来改善慢性脑灌注不足后的海马神经元损伤
DOI：
10.1007/s12640-019-00141-8
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发表时间：
2019-12-05
影响因子：
3.7
通讯作者：
Hai, Jian
中科院分区：
文献类型：
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作者：
Wang, Da-Peng;Lv, Qiao-Li;Hai, Jian
慢性脑灌注不足（CCH）是导致阿尔茨海默病、血管性痴呆和衰老的认知能力下降和退行性过程的主要因素。然而，cch诱导的神经元损伤的微妙机制，因此适当的治疗，仍然不清楚。WIN55,212-2 （WIN）是一种非选择性大麻素受体激动剂，已被证明对海马神经元存活有影响。在本研究中，我们研究了WIN在双侧颈总动脉闭塞大鼠CCH模型中的潜在作用及其潜在机制。苏木精染色、伊红染色及电镜观察海马形态变化及线粒体超微结构变化。各种生物标志物，如活性氧物质（ROS）、超氧化物歧化酶（SOD）、过氧化氢酶（CAT）和丙二醛（MDA）被用来评估海马的氧化应激水平。此外，通过western blotting检测神经元核（NeuN）、凋亡信号调节激酶1 (ASK1)-p38信号蛋白、cleaved Caspase-9和-3以及细胞色素c （Cyt-C）的表达水平。CCH降低了NeuN、Cyt-C（线粒体）、SOD和CAT的水平，增加了MDA、磷酸化ASK1和磷酸化p38、裂解Caspase-9和-3和Cyt-C（细胞质）的水平，这些被WIN处理逆转。长期用WIN治疗也能改善cch诱导的神经元变性和线粒体断裂。这些发现表明，WIN可能是缺血性神经元损伤的潜在治疗剂，其机制与氧化应激和ASK1-p38信号的抑制有关。
Chronic cerebral hypoperfusion (CCH) is a major contributor to cognitive decline and degenerative processes leading to Alzheimer's disease, vascular dementia, and aging. However, the delicate mechanism of CCH-induced neuronal damage, and therefore proper treatment, remains unclear. WIN55,212-2 (WIN) is a nonselective cannabinoid receptor agonist that has been shown to have effects on hippocampal neuron survival. In this study, we investigated the potential roles of WIN, as well as its underlying mechanism in a rat CCH model of bilateral common carotid artery occlusion. Hippocampal morphological changes and mitochondrial ultrastructure were detected using hematoxylin and eosin staining and electron microscopy, respectively. Various biomarkers, such as reactive oxidative species (ROS), superoxide dismutase (SOD), catalase (CAT), and malondialdehyde (MDA) were used to assess the level of oxidative stress in the hippocampus. Furthermore, the expression levels of neuronal nuclei (NeuN), apoptosis signal-regulating kinase 1 (ASK1)-p38 signaling proteins, cleaved Caspase-9 and -3, and cytochrome-c (Cyt-C) were accessed by western blotting. CCH decreased the levels of NeuN, Cyt-C (mitochondrial), SOD, and CAT, and increased the levels of MDA, phosphorylated ASK1 and phosphorylated p38, cleaved Caspase-9 and -3, and Cyt-C (cytoplasm), which were reversed by WIN treatment. Chronic treatment with WIN also improved CCH-induced neuronal degeneration and mitochondrial fragmentation. These findings indicated that WIN may be a potential therapeutic agent for ischemic neuronal damage, involving a mechanism associated with the suppression of oxidative stress and ASK1-p38 signaling.