Lin Zhongqiao, Lu Yan, Li Sheng, Li Yiying, Li Han, Li Lin, Wang Lei
Department of Geriatrics, Third Hospital of Shanxi Medical University, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences Taiyuan 030032, Shanxi, China.
Department of Physiology, Key Laboratory of Cellular Physiology, Ministry of Education, Shanxi Medical University Taiyuan 030001, Shanxi, China.
Am J Transl Res. 2022 Jun 15;14(6):3864-3878. eCollection 2022.
The present study aimed to determine the effect of blocking brain mineralocorticoid receptor on cognitive impairment in spontaneously hypertensive rats and its intracellular changes.
12-week-old male spontaneous hypertensive rats (SHR) and Wistar Kyoto (WKY) rats were given eplerenone (EPL, 30 mg/Kg/d or 100 mg/Kg/d) or pure water via oral gavage daily for 8 weeks. Effects of blocking brain mineralocorticoid receptor (MR) on cognitive function were examined through cognitive behavioral experiments. The morphology of hippocampal neurons was observed. Synaptic proteins and autophagy levels were detected by western blot.
The results showed decreases in both short-term working memory and long-term spatial learning and memory ability, hippocampal neuron damage, and reduced expression of synaptic proteins in the SHR-Veh group. Impaired autophagy was found in the SHR-Veh group as evidenced by decreased expression levels of Beclin-1 protein and a defect in P62 degradation. These abnormalities were reversed by eplerenone, either the high dosage or low dosage. Reduced cognitive dysfunction and enhanced autophagy in hippocampal neurons in both SHR-EPL30 group and SHR-EPL100 group were independent of lowering blood pressure.
Eplerenone improves cognitive deficits observed in SHRs, and increases autophagy in hippocampal neurons of SHRs, which suggests a new site of MR antagonists in treatment of hypertension-related cognitive impairment.
本研究旨在确定阻断脑盐皮质激素受体对自发性高血压大鼠认知功能障碍的影响及其细胞内变化。
12周龄雄性自发性高血压大鼠（SHR）和Wistar Kyoto（WKY）大鼠每天经口灌胃给予依普利酮（EPL，30mg/Kg/d或100mg/Kg/d）或纯水，持续8周。通过认知行为实验检测阻断脑盐皮质激素受体（MR）对认知功能的影响。观察海马神经元的形态。通过蛋白质免疫印迹法检测突触蛋白和自噬水平。
结果显示，SHR-Veh组的短期工作记忆以及长期空间学习和记忆能力均下降，海马神经元受损，突触蛋白表达减少。SHR-Veh组存在自噬受损，表现为Beclin-1蛋白表达水平降低和P62降解缺陷。高剂量或低剂量依普利酮均可逆转这些异常。SHR-EPL30组和SHR-EPL100组海马神经元的认知功能障碍减轻且自噬增强，这与血压降低无关。
依普利酮可改善SHR中观察到的认知缺陷，并增加SHR海马神经元中的自噬，这提示MR拮抗剂在治疗高血压相关认知障碍方面有新的作用位点。
