Department of Pharmacology, Biomedical Science Institute and Medical Science and Engineering Research Center for Bioreaction to Reactive Oxygen Species, School of Medicine, Kyung Hee University, Seoul 130-071, Republic of Korea.
J Endocrinol. 2010 Jun;205(3):263-70. doi: 10.1677/JOE-10-0040. Epub 2010 Mar 29.
Ghrelin is an endogenous ligand for GH secretagogue receptor type 1a (GHSR1a), and is produced and released mainly from the stomach. It has been recently demonstrated that ghrelin can function as a neuroprotective factor by inhibiting apoptotic pathways. Kainic acid (KA), an excitatory amino acid l-glutamate analog, causes neuronal death in the hippocampus; previous studies suggest that activated microglia and astrocytes actively participate in the pathogenesis of KA-induced hippocampal neurodegeneration. However, it is unclear whether ghrelin has neuroprotective effect in KA-induced hippocampal neurodegeneration. I.p. injection of KA produced typical neuronal cell death in the CA1 and CA3 pyramidal layers of the hippocampus, and the systemic administration of ghrelin significantly attenuated KA-induced neuronal cell death in these regions through the activation of GHSR1a. Ghrelin prevents KA-induced activation of microglia and astrocytes, and the expression of proinflammatory mediators tumor necrosis factor alpha, interleukin-1beta, and cyclooxygenase-2. The inhibitory effect of ghrelin on the activation of microglia and astrocytes appears to be associated with the inhibition of matrix metalloproteinase-3 expression in damaged hippocampal neurons. Our data suggest that ghrelin has a therapeutic potential for suppressing KA-induced pathogenesis in the brain.
胃饥饿素是生长激素促分泌素受体 1a（GHSR1a）的内源性配体，主要由胃产生和释放。最近的研究表明，胃饥饿素可以通过抑制凋亡途径发挥神经保护作用。海人酸（KA），一种兴奋性氨基酸 L-谷氨酸类似物，可导致海马神经元死亡；先前的研究表明，激活的小胶质细胞和星形胶质细胞积极参与 KA 诱导的海马神经退行性变的发病机制。然而，胃饥饿素是否对 KA 诱导的海马神经退行性变具有神经保护作用尚不清楚。腹腔内注射 KA 可在海马 CA1 和 CA3 锥体层产生典型的神经元细胞死亡，而全身性给予胃饥饿素可通过激活 GHSR1a 显著减轻这些区域的 KA 诱导的神经元细胞死亡。胃饥饿素可防止 KA 诱导的小胶质细胞和星形胶质细胞激活以及促炎介质肿瘤坏死因子-α、白细胞介素-1β和环加氧酶-2 的表达。胃饥饿素对小胶质细胞和星形胶质细胞激活的抑制作用似乎与抑制受损海马神经元中基质金属蛋白酶-3 的表达有关。我们的数据表明，胃饥饿素具有抑制 KA 诱导的脑内发病机制的治疗潜力。
