Andrews Zane B, Erion Derek, Beiler Rudolph, Liu Zhong-Wu, Abizaid Alfonso, Zigman Jeffrey, Elsworth John D, Savitt Joseph M, DiMarchi Richard, Tschoep Matthias, Roth Robert H, Gao Xiao-Bing, Horvath Tamas L
Department of Obstetrics, Gynecology & Reproductive Sciences, Yale University School of Medicine, New Haven, Connecticut 06520, USA.
J Neurosci. 2009 Nov 11;29(45):14057-65. doi: 10.1523/JNEUROSCI.3890-09.2009.
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, reactive oxygen species production, and biogenesis. Together, our data reveal 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.
胃饥饿素作用于下丘脑以调节食物摄入和肥胖。内源性胃饥饿素受体[生长激素促分泌素受体(GHSR)]也存在于下丘脑外的部位，在这些部位它们促进与学习、记忆和奖赏寻求行为相关的神经回路活动。在此，我们表明黑质致密部(SNpc)，即多巴胺(DA)细胞变性导致帕金森病(PD)的脑区，表达GHSR。胃饥饿素与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。给予外源性胃饥饿素可减少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，并限制纹状体多巴胺的损失。胃饥饿素或胃饥饿素受体(GHSR)的基因敲除增加了MPTP处理后SNpc DA细胞的损失并降低了纹状体多巴胺水平，而儿茶酚胺能神经元中GHSR的选择性重新激活可逆转这一效应。胃饥饿素诱导的神经保护作用通过解偶联蛋白2(UCP2)依赖的线粒体呼吸、活性氧生成和生物发生的改变依赖于线粒体氧化还原状态。总之，我们的数据表明外周胃饥饿素通过激活UCP2依赖的线粒体机制在维持和保护正常黑质纹状体多巴胺功能中起重要作用。这些研究支持胃饥饿素作为对抗与PD相关的神经退行性变、食欲不振和体重减轻的一种新的治疗策略。最后，我们讨论了这些研究对肥胖与神经退行性变之间联系的潜在影响。
