Preservation of spatial memory and neuroprotection by the fatty acid amide hydrolase inhibitor URB597 in a rat model of vascular dementia.
Preservation of spatial memory and neuroprotection by the fatty acid amide hydrolase inhibitor URB597 in a rat model of vascular dementia.
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脂肪酸酰胺水解酶抑制剂URB597在血管性痴呆大鼠模型中对空间记忆和神经保护的保护作用
DOI：
10.21037/atm-20-4431
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发表时间：
2021-03
影响因子：
--
通讯作者：
Hai J
中科院分区：
文献类型：
--
作者：
Wang DP;Lin Q;Kang K;Wu YF;Su SH;Hai J
慢性脑灌注不足（CCH）是血管性痴呆（VaD）的主要危险因素。目前还没有广泛有效的VaD预防或治疗策略，但最近的研究报告了血管旁路手术和大脑内源性大麻素系统（ECS）药物调节后的良好结果。在这项研究中，脑肌血管病（EMS）搭桥手术和增强内源性大麻素信号对CCH诱导的认知功能障碍和神经元损伤的早期影响进行了研究。采用双侧颈总动脉夹闭（BCCAO）法建立VaD动物模型。大麻素信号通过用脂肪酸酰胺水解酶抑制剂URB 597（URB）处理而上调。比较Sham、BCCAO、BCCAO + EMS、BCCAO + UR B和BCCAO + UR B + EMS组的空间学习和记忆、脑血流量（CBF）、血管重建、脑源性神经营养因子（BDNF）-原肌球蛋白受体激酶B（Trk B）信号传导和细胞凋亡。采用Morris水迷宫（MWM）评价大鼠的空间学习记忆能力。采用三维动脉自旋标记法测定皮层和海马脑血流。通过CD 34免疫荧光染色观察新生血管形成，并通过Western印迹法评估BDNF-TrkB信号蛋白表达水平。用URB 597而不是EMS单独治疗逆转了BCCAO诱导的空间学习和记忆缺陷。EMS手术后新生血管增强，但URB 597没有。或者，治疗组间CBF无显著差异。与Sham处理相比，CCH显著降低了BDNF和TrkB的表达水平，URB 597处理逆转了这两种蛋白质的下调，但EMS没有逆转。BCCAO增强神经元凋亡，这也被URB 597逆转。内源性大麻素信号的增强而不是EMS保护免受CCH诱导的神经变性，并可能通过激活BDNF-TrkB信号来保护空间学习和记忆。
Chronic cerebral hypoperfusion (CCH) is a major risk factor for vascular dementia (VaD). There are currently no broadly effective prevention or treatment strategies for VaD, but recent studies have reported promising results following vascular bypass surgery and pharmacomodulation of the brain endocannabinoid system (ECS). In this study, early effects of encephalomyosynangiosis (EMS) bypass surgery and augmented endocannabinoid signaling on CCH-induced cognitive dysfunction and neuronal damage were investigated. An animal model of VaD was established by bilateral common carotid artery occlusion (BCCAO). Cannabinoid signaling was upregulated by treatment with the fatty acid amide hydrolase inhibitor URB597 (URB). Spatial learning and memory, cerebral blood flow (CBF), revascularization, brain-derived neurotrophic factor (BDNF)-tropomyosin receptor kinase B (TrkB) signaling, and apoptosis were compared among Sham, BCCAO, BCCAO + EMS, BCCAO + URB, and BCCAO + URB + EMS groups. Spatial learning and memory were evaluated using the Morris water maze (MWM). The CBF in cortex and hippocampus was evaluated by 3-dimensional arterial spin labeling. The neovascularization was visualized by CD34 immunofluorescence staining, and BDNF-TrkB signaling protein expression levels were assessed by Western blotting. Treatment with URB597 but not EMS alone reversed the spatial learning and memory deficits induced by BCCAO. Neovascularization was enhanced after EMS surgery but not by URB597. Alternatively, there were no significant differences in CBF among treatment groups. Expression levels of BDNF and TrkB were significantly reduced by CCH compared to Sham treatment, and downregulation of both proteins was reversed by URB597 treatment but not EMS. BCCAO enhanced neuronal apoptosis, which was also reversed by URB597. Augmentation of endogenous cannabinoid signaling but not EMS protects against CCH-induced neurodegeneration and preserves spatial learning and memory, possibly by activating BDNF-TrkB signaling.
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