Ghrelin promotes and protects nigrostriatal dopamine function via a UCP2-dependent mitochondrial mechanism.
Ghrelin promotes and protects nigrostriatal dopamine function via a UCP2-dependent mitochondrial mechanism.
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DOI：
10.1523/jneurosci.3890-09.2009
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发表时间：
2009-11-11
期刊：
影响因子：
--
通讯作者：
Horvath TL
中科院分区：
文献类型：
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作者：
Andrews ZB;Erion D;Beiler R;Liu ZW;Abizaid A;Zigman J;Elsworth JD;Savitt JM;DiMarchi R;Tschoep M;Roth RH;Gao XB;Horvath TL
Ghrelin靶向下丘脑以调节食物摄入和肥胖。内源性生长激素释放肽受体（生长激素促分泌素受体，GHSR）也存在于下丘脑外部位，在那里它们促进与学习和记忆相关的回路活动，以及奖励寻求行为。在这里，我们表明黑质致密部（SNpc）是多巴胺（DA）细胞变性导致帕金森病（PD）的大脑区域，表达GHSR。Ghrelin与SNpc细胞结合，电激活SNpc DA神经元，增加酪氨酸羟化酶mRNA并增加背侧纹状体中的DA浓度。外源性Ghrelin给药减少了1-甲基-4-苯基-1，2，5，6-四氢吡啶（MPTP）处理后SNpc DA细胞的损失和限制纹状体多巴胺的损失。基因消融生长激素释放肽或生长激素释放肽受体（GHSR）增加SNpc DA细胞损失和降低纹状体多巴胺水平MPTP治疗后，在儿茶酚胺能神经元GHSR的选择性再激活逆转的效果。Ghrelin诱导的神经保护作用依赖于线粒体氧化还原状态，通过解偶联蛋白2（UCP 2）依赖的线粒体呼吸，ROS产生和生物合成的改变。总之，我们的数据表明，外周ghrelin起着重要的作用，在维护和保护正常的黑质纹状体多巴胺功能，通过激活UCP 2依赖的线粒体机制。这些研究支持ghrelin作为一种新的治疗策略，以对抗与PD相关的神经变性，食欲不振和体重下降。最后，我们讨论了这些研究对肥胖和神经退行性变之间联系的潜在影响。
Ghrelin targets the hypothalamus to regulate food intake and adiposity. Endogenous ghrelin receptors (growth hormone secretagogue receptor, GHSR) are also present in extrahypothalamic sites where they promote circuit activity associated with learning and memory, and reward seeking behavior. Here, we show that the substantia nigra pars compacta (SNpc), a brain region where dopamine (DA) cell degeneration leads to Parkinson’s disease (PD), expresses GHSR. Ghrelin binds to SNpc cells, electrically activates SNpc DA neurons, increases tyrosine hydroxylase mRNA and increases DA concentration in the dorsal striatum. Exogenous ghrelin administration decreased SNpc DA cell loss and restricted striatal dopamine loss after 1-methyl-4-phenyl-1,2,5,6 tetrahydropyridine (MPTP) treatment. Genetic ablation of ghrelin or the ghrelin receptor (GHSR) increased SNpc DA cell loss and lowered striatal dopamine levels after MPTP treatment, an effect that was reversed by selective reactivation of GHSR in catecholaminergic neurons. Ghrelin-induced neuroprotection was dependent on the mitochondrial redox state via uncoupling protein 2 (UCP2)-dependent alterations in mitochondrial respiration, ROS production and biogenesis. Taken together, our data reveals that peripheral ghrelin plays an important role in the maintenance and protection of normal nigrostriatal dopamine function by activating UCP2-dependent mitochondrial mechanisms. These studies support ghrelin as a novel therapeutic strategy to combat neurodegeneration, loss of appetite and body weight associated with PD. Finally, we discuss the potential implications of these studies on the link between obesity and neurodegeneration.