Dopamine D2 receptor agonist Bromocriptine ameliorates Aβ1-42-induced memory deficits and neuroinflammation in mice

神经炎症 莫里斯水上航行任务 溴隐亭 兴奋剂 多巴胺受体D2 多巴胺能 多巴胺 医学 促炎细胞因子 药理学 内分泌学 内科学 受体 炎症 海马体 激素 催乳素
作者
Xin Liu,Ling He,Yanfeng Li,Chao Liu,Chen Wang,Xiaojian Gong,Ling He
出处
期刊:European Journal of Pharmacology [Elsevier]
卷期号:938: 175443-175443 被引量:11
标识
DOI:10.1016/j.ejphar.2022.175443
摘要

Alzheimer's Disease (AD) is the most common neurodegenerative disease, which lacks disease-modifying therapeutics so far. Studies have shown that the dysfunction of the dopaminergic system is related to a variety of pathophysiology of AD, and the expression of Dopamine D2 receptor (DRD2) in the brains of AD patients and animal models is significantly downregulated, suggesting that DRD2 may represent a therapeutic target for AD. However, the strategy of targeting DRD2 for AD treatment still lacks some key experimental evidences. Here we show that DRD2 agonist Bromocriptine improved Aβ1-42 induced neuroinflammation, neuronal apoptosis, and memory deficits in mice. For animal study, the mice have injected intracerebroventricularly (i.c.v.) with Aβ1-42(410 pmol/5 μl) to induced AD cognitive deficit model (Mazzola et al., 2003; van der Stelt et al., 2006). After 7 days, Bromocriptine (2.5 mg/kg, 5 mg/kg and 10 mg/kg) or normal saline was administered intragastrically once a day for 30 days. Behavioral tests about the Y maze and Morris water maze in mice were initiated on the twenty-fourth day of drug administration for 7 days. In vivo and in vitro mechanism research revealed that Bromocriptine, via activating DRD2, promoted the recruitment of PP2A and JNK by scaffold protein β-arrestin 2, that repressed JNK-mediated transcription of proinflammatory cytokines and activation of NLRP3 inflammasome in microglia. Collectively, our findings suggest that Bromocriptine can ameliorate Aβ1-42 induced neuroinflammation and memory deficits in mice through DRD2/β-arrestin 2/PP2A/JNK signaling axis, which provides an experimental basis for the development of Bromocriptine as a drug for AD.
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