脂肪酰胺水解酶抑制剂URB597对慢性脑低灌注大鼠自噬过程的调控作用及机制研究

Chronic cerebral hypoperfusion (CCH),which is associated with several ischemic cerebrovascular diseases, may lead to cognitive impairment and social dysfunction in patients. It remains unknown how to prevent the cognitive deterioration associated with CCH clinically. Autophagy, the process of self-degradation of cellular components, is a double-edged sword. Abnormal autophagy process is associated with various kinds of neuronal damage. To our knowledge, the studies with respect to the impact of autophagy process on neuronal cells under chronic cerebral ischemia are scarce. Moreover, the effect of autophagy process in experimental models of cerebral ischemia is controversial. In this study, based on neuronal histology, neuronal behavior, molecular biology,etc, we try to investigate the effects of autophagy process on the neuronal cells under the condition of CCH. In addition, our previous studies demonstrated that treatment of URB597, a selective inhibitor of fatty acid amide hydrolyase (FAAH) for the degradation of endocannabinoid ligands, can reverse CCH-induced neuronal apoptosis,neuroinflammatory responses and cognitive deficits, indicating the neuroprotective effect of URB597. In this study, we further investigate the effect of URB597 on the autophagy process in rats with CCH and the potential mechanism underlying its action, which might enable us to find a novel strategy and provide the new evidence for the repair of ischemic neuronal damage.

慢性脑低灌注（CCH）与多种缺血性脑血管病的病理发生密切相关，临床上尚缺乏有效的干预措施，是导致患者认知功能障碍和社会行为能力低下的重要因素。自噬是一把双刃剑，异常的自噬过程与神经细胞的各种损伤也密切相关。目前国内外关于颅内慢性缺血状态下自噬过程对神经细胞的影响尚缺乏深入研究，有限的研究结果也有较大的争议。本项目拟以整体动物为研究对象，从神经组织学、神经行为学、分子生物学等多维层面，考察在CCH状态下自噬过程对神经细胞的影响。此外，我们前期研究发现大麻素内源性配基失活系统化合物即脂肪酰胺水解酶抑制剂URB597可明显降低神经细胞凋亡及炎症反应，改善认知功能障碍，提示URB597这种抑制内源性大麻素失活系统的化合物具有一定的神经保护作用。本项目拟进一步考察URB597对慢性脑低灌注动物自噬过程的影响及相关机制，有助于发现药物干预的新靶点，为改善患者在CCH状态下神经功能损伤提供科学依据。

本课题通过对大鼠慢性脑低灌注( Chronic cerebral hypoperfusion，CCH) 动物模型的研究发现自噬在CCH导致的神经细胞死亡的过程中发挥了一定的作用。CCH诱导了溶酶体功能障碍，由于溶酶体功能的障碍导致了自噬体-溶酶体的结合困难，导致了自噬体的堆积，最终导致了异常的过度自噬。此不正常的自噬可导致了突出后密度处泛素化蛋白的堆积，最终导致了突出可塑性的损伤甚至导致了认知功能的障碍。BNIP-3-cyt C通路及parkin通路参与了CCH线粒体自噬的过程。JNK通路同样也参与了CCH导致的过度自噬。然而，URB597通过抑制受损的自噬潮及beclin-1/Bcl-2复合体的分离，并且切断BNIP-3-cyt C通路及parkin通路来抑制不正常的过度自噬。此外，CCH诱导的溶酶体功能障碍可导致NLRP3炎性小体的激活及IL-1β的释放。小胶质过度增生、ROS堆积是CCH异常过度自噬的上游调控机制。然而,UBR597可通过改善溶酶体功能、抑制小胶质增生及ROS堆积来减轻异常过度自噬来缓解上述神经损伤，这表明了URB597可以通过抑制CCH导致的异常自噬来发挥神经保护的作用。

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