FAAH抑制剂URB597调控ERS改善慢性脑低灌注大鼠认知功能障碍的作用及机制研究

慢性脑低灌注（CCH）是缺血性脑血管病的基本血流动力学特征，可诱导血管性认知功能障碍，其作用机制尚不明确。内质网应激（ERS）参与炎症、氧化应激和线粒体功能的调控，与多种神经系统疾病的病理发生密切相关。前期研究发现：脂肪酰胺水解酶（FAAH）抑制剂URB597对缺血性脑损伤具有抗炎和抗氧化作用、抑制ERS相关蛋白GRP78和CHOP表达、改善内质网与线粒体膜偶联区域超微结构损伤；凋亡信号调节激酶1（ASK1）和核因子E2相关因子2（Nrf2）信号通路在ERS中起关键作用。我们推测在CCH状态下，URB597可能通过ASK1/JNK和（或）Nrf2/HO-1信号通路调控ERS而发挥神经保护作用。本项目拟通过体内外实验，采用神经组织学、神经行为学、分子生物学等技术方法，系统研究URB597改善CCH大鼠认知功能障碍的ERS调控作用及相关机制，可望为缺血性神经损伤修复和功能重建提供新靶点。

Chronic cerebral hypoperfusion (CCH), the basic hemodynamic characteristic of ischemic cerebrovascular diseases, may lead to vascular cognitive impairment, but the mechanism remains unclear. Endoplasmic reticulum stress (ERS) associates with pathological processes of many neurological disorders, involving in the regulation of inflammatory response, oxidative stress, and mitochondrial function. We previously found that the fatty acid amide hydrolase (FAAH) inhibitor URB597 ameliorated CCH-induced cerebral damage by suppressing neuroinflammation, oxidative stress, expressions of GRP78 and CHOP, and ultrastructural deterioration of endoplasmic reticulum and mitochondria-associated membranes. Furthermore, ASK1 and Nrf2 signaling pathways play key roles in ERS during cerebral ischemia. Therefore, it is speculated that URB597 may show a potential neuroprotective effect against CCH-induced cognitive dysfunction that may be mediated by ERS through ASK1/JNK or Nrf2/HO-1 signaling pathway. In present study, the effects of URB597 on ERS regulation, as well as the underlying mechanisms in improving chronic ischemic cognitive dysfunction will be further investigated, using neuronal histology, neuronal behavior, and molecular biology in vivo and vitro experiments in rats with CCH. This study will enable us to find a novel target for the repair of ischemic neuronal injury and reconstruction of neuronal function.