Simvastatin reverses the downregulation of M1/4 receptor binding in 6-hydroxydopamine-induced parkinsonian rats: The association with improvements in long-term memory
Simvastatin reverses the downregulation of M1/4 receptor binding in 6-hydroxydopamine-induced parkinsonian rats: The association with improvements in long-term memory
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DOI：
10.1016/j.neuroscience.2014.02.031
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发表时间：
2014-05
期刊：
影响因子：
3.3
通讯作者：
Qing Wang;Qing Wang;Xiaobo Wei;Huimin Gao;Jin Li;J. Liao;Xu Liu;B. Qin;Yinghua Yu;Chao Deng;B. Tang;Xu-Feng Huang
中科院分区：
文献类型：
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作者：
Qing Wang;Qing Wang;Xiaobo Wei;Huimin Gao;Jin Li;J. Liao;Xu Liu;B. Qin;Yinghua Yu;Chao Deng;B. Tang;Xu-Feng Huang
研究认为，毒蕈碱M1/4受体与多巴胺能系统密切相关，在帕金森病（PD）的发病过程中起重要作用。除了调节脂质代谢和预防中风外，他汀类药物还被用于调节认知能力下降。我们旨在探讨6-羟多巴胺（6-OHDA）损伤大鼠脑中M1/4受体的区域变化。方法采用单侧内侧前脑束注射6-羟多巴胺建立spd大鼠模型；而辛伐他汀（10 mg/kg/天）或生理盐水分别口服3周。用Morris水迷宫测量长期记忆。[3H]应用吡仑西平结合放射自显影技术研究PD大鼠脑内M1/4受体的变化。结果6-羟多巴胺诱导大鼠海马、杏仁核内侧、后内侧皮质和梨状皮质M1/4受体下调，引起大鼠长期记忆缺损；辛伐他汀可显著改善大鼠记忆障碍，逆转M1/4受体下调。辛伐他汀治疗后，长期记忆活动的下降与不同脑区M1/4受体的恢复之间存在显著的正相关。结论/意义我们的研究结果提供了强有力的证据，证明辛伐他汀给药后M1/4受体的调节确实，至少部分地有助于6-羟多巴胺诱导的PD大鼠长期记忆的改善。这些结果为辛伐他汀通过M1/4受体治疗PD等精神神经疾病提供了可能的机制。
BackgroundIt is believed that muscarinic M1/4 receptors are closely correlated to the dopaminergic system and are strongly involved in the pathogenesis of Parkinson’s disease (PD). In addition to regulating lipid metabolism and protection from stroke, statins have been used to regulate the declined cognition. We aimed to explore the regional changes in M1/4 receptors in the 6-hydroxydopamine (6-OHDA)-lesioned rat brain.MethodsPD rat model was set up by injecting 6-OHDA into the unilateral medial forebrain bundle; while simvastatin (10 mg/kg/day) or saline was orally administrated for 3 weeks, respectively. Long-term memory was measured using the Morris water maze. [3H]pirenzepine binding autoradiography was applied to investigate the alterations of M1/4 receptors in the PD rat brains.Results6-OHDA induced long-term memory deficits along with downregulation of M1/4 receptors in the hippocampus, the medial amygdala, the posteromedial cortical and the piriform cortex; simvastatin administration significantly ameliorated the impaired memory and reversed the downregulation of M1/4 receptors in the examined brain regions. Profound positive correlations were verified between the decline in long-term memory activity and the restoration of M1/4 receptors in different brain regions after simvastatin treatment.Conclusions/significanceOur results provide strong evidence that M1/4 receptor modulation after simvastatin administration did, at least partially, contribute to the improvement in the long-term memory in 6-OHDA-induced PD rats. These results provide a possible mechanism for simvastatin treatment in psycho-neurological diseases such as PD via M1/4 receptors.