5-HT_(2A)受体反向激动剂LPM6690061对AD大鼠精神病性症状的治疗作用及机制  

Therapeutic Effect and Mechanism of 5-HT_(2A) Receptor Reverse Agonist LPM6690061 on Psychiatric Symptoms in Alzheimer’s Disease(AD)Rats

作　　者：杨月 张晓璠 朱晓音[1] 田京伟[1] YANG Yue;ZHANG Xiaofan;ZHU Xiaoyin;TIAN Jingwei(School of Pharmacy,Key Laboratory of Molecular Pharmacology and Drug Evaluation(Yantai University),Ministry of Education,Collaborative Innovation Center of Advanced Drug Delivery System and Biotech Drugs in Universities of Shandong,Yantai University,Yantai 264005,China)

机构地区：[1]烟台大学药学院,分子药理和药物评价教育部重点实验室(烟台大学),新型制剂与生物技术药物研究山东省高校协同创新中心,山东烟台264005

出　　处：《烟台大学学报（自然科学与工程版）》2024年第4期446-453,共8页Journal of Yantai University(Natural Science and Engineering Edition)

基　　金：泰山学者项目(2207070499,主持人:赵克浩)。

摘　　要：旨在研究5-HT_(2A)受体反向激动剂LPM6690061对阿尔茨海默伴发精神病性症状大鼠模型的作用及其相关作用机制。建立双侧海马注入β-淀粉样蛋白(Aβ)AD大鼠模型,采用DOI诱导AD大鼠出现精神病相关行为表型,灌胃给予3.0 mg/kg LPM6690061进行体内药效学及机制研究。采用Western Blot(WB)检测LPM6690061对磷酸化蛋白激酶B(P-AKT)、磷酸化环磷腺苷效应元件结合蛋白(P-CREB)、脑源性神经营养因子(Brain-derived neurotrophic factor,BDNF)在海马中表达水平的影响;采用尼氏染色观察海马区神经细胞形态和数量的改变;高尔基染色检测LPM6690061对大鼠海马树突棘密度的影响。结果表明,LPM6690061可显著减轻DOI诱导的大鼠甩头。在新物体识别试验中,LPM6690061显著改善了Aβ引起的认知障碍。前脉冲抑制测试中,LPM6690061显著提高了ADP大鼠的前脉冲抑制率。LPM6690061可增加ADP大鼠海马区P-AKT、P-CREB、BDNF的蛋白表达水平,增加海马区神经元数量,显著缓解由聚集态Aβ造成的树突棘密度降低。上述研究结果表明,LPM6690061可以通过AKT/CREB/BDNF途径改善由Aβ沉积对突触可塑性的影响,从而减轻ADP大鼠精神症状,改善ADP大鼠认知障碍。This article aimed to investigate the effects and related mechanisms of the 5-HT_(2A) receptor reverse agonist LPM6690061 on a rat model of psychosis in Alzheimer’s disease(ADP).A bilateral hippocampal injection ofβ-Amyloid protein(Aβ)was used to establish an AD rat model,and DOI was used to induce psychopathic behavior phenotypes in AD rats.Oral administration of 3.0 mg/kg LPM6690061 was used for in vivo pharmacological and mechanistic studies.The effects of LPM6690061 on the expression levels of phosphorylated protein kinase B(P-AKT),phosphorylated cyclic adenosine monophosphate effector element binding protein(P-CREB),and brain-derived neurotrophic factor(BDNF)in the hippocampus were examined by Western Blot(WB).Nissl staining was utilized to observe changes in the neuronal morphology and quantity of the hippocampal neurocytes.Golgi-Cox staining was employed to assess the impact of LPM6690061 on the dendritic spine density in the hippocampus of rats.The results indicated that LPM6690061 significantly alleviated DOI-induced head-twitch response in rates.In the new object recognition test,LPM6690061 significantly improves cognitive impairments caused by Aβ.In the pre-pulse inhibition test,LPM6690061 significantly enhanced the pre-pulse inhibition rate in ADP rats.LPM6690061 increased the protein expression levels of P-AKT,P-CREB,and BDNF in the hippocampal region of AD rates,increased the number of neurons in the hippocampus,and significantly alleviated the decrease in dendritic spine density caused by aggregated Aβ.These findings suggest that LPM6690061 can improve the synaptic plasticity affected by Aβdeposition through the AKT/CREB/BDNF pathway,thereby alleviating psychotic symptoms and improving cognitive impairments in ADP rats.

关 键 词：阿尔茨海默伴发精神病性症状 5-HT_(2A)受体 BDNF 突触可塑性 

分 类 号：R964[医药卫生—药理学]