Centre for Drug Research, Universiti Sains Malaysia, Penang, Malaysia.
Department of Psychiatry and Psychotherapy, University Clinic, Friedrich-Alexander-University of Erlangen-Nuremberg, Erlangen, Germany.
Pharmacol Rep. 2019 Jun;71(3):443-448. doi: 10.1016/j.pharep.2019.01.012. Epub 2019 Jan 30.
Chronic cerebral hypoperfusion (CCH) can induce the accumulation of reactive oxygen species, which leads to oxidative damage, neuronal injury, and central cholinergic dysfunction in vulnerable regions of the brain, such as the hippocampus and cerebral cortex. These effects can lead to significant cognitive impairments in clinical populations of vascular dementia (VaD). The present studies aimed to investigate the role of the cholinergic system in memory functions and hippocampal long-term potentiation (LTP) impairments induced by CCH in rats.
Male Sprague Dawley rats were subjected to permanent bilateral occlusion of common carotid arteries (PBOCCA) or sham surgery. Then, PBOCCA rats received ip injections with, either vehicle (control group), the muscarinic receptor agonist oxotremorine (0.1 mg/kg), or the acetylcholinesterase inhibitor physostigmine (0.1 mg/kg). Cognitive functions were evaluated using a passive avoidance task and the Morris water maze test. In addition, hippocampal LTP was recorded in vivo under anaesthesia.
The PBOCCA rats exhibited significant deficits in passive avoidance retention and spatial learning and memory tests. They also showed a suppression of LTP formation in the hippocampus. Oxotremorine and physostigmine significantly improved the learning and memory deficits as well as the suppression of LTP in PBOCCA rats.
The present data suggest that the cholinergic system plays an important role in CCH-induced cognitive deficits and could be an effective therapeutic target for the treatment of VaD.
慢性脑灌注不足（CCH）可引起活性氧的积累，导致氧化损伤、神经元损伤和中枢胆碱能功能障碍，易损区如海马和大脑皮层。这些影响可导致血管性痴呆（VaD）临床人群的认知功能显著受损。本研究旨在探讨胆碱能系统在 CCH 诱导的大鼠记忆功能和海马长时程增强（LTP）损伤中的作用。
雄性 Sprague Dawley 大鼠行双侧颈总动脉永久性闭塞术（PBOCCA）或假手术。然后，PBOCCA 大鼠给予腹腔注射，载体（对照组）、毒蕈碱受体激动剂 Oxotremorine（0.1mg/kg）或乙酰胆碱酯酶抑制剂毒扁豆碱（0.1mg/kg）。采用被动回避任务和 Morris 水迷宫测试评估认知功能。此外，在麻醉下体内记录海马 LTP。
PBOCCA 大鼠在被动回避保留和空间学习记忆测试中表现出明显的缺陷。它们还显示海马 LTP 形成受到抑制。Oxotremorine 和毒扁豆碱显著改善了 PBOCCA 大鼠的学习记忆缺陷以及 LTP 的抑制。
本研究数据表明，胆碱能系统在 CCH 诱导的认知缺陷中起重要作用，可能是治疗 VaD 的有效治疗靶点。
