Excitotoxic degeneration of hypothalamic orexin neurons in slice culture
Excitotoxic degeneration of hypothalamic orexin neurons in slice culture
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DOI：
10.1016/j.nbd.2003.09.003
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发表时间：
2004-02-01
影响因子：
6.1
通讯作者：
Akaike, A
中科院分区：
文献类型：
--
作者：
Katsuki, H;Akaike, A
多条证据表明，发作性睡病是一种睡眠障碍，其原因是下丘脑中含有增食欲素(下丘脑)的神经元丢失，但选择性消除这种神经元的机制尚不清楚。利用器官型大鼠下丘脑脑片培养，我们研究了增食欲素神经元对兴奋性毒性侮辱的易感性。与N-甲基-D-天冬氨酸(NMDA)孵育24小时，然后恢复72小时，食欲素免疫反应神经元的数量显著减少，而黑素浓缩激素(MCH)免疫反应神经元的数量相对较少。相反，增食欲素神经元比MCH神经元更能抵抗红藻氨酸的细胞毒性。对几种内源性谷氨酸受体激动剂以及谷氨酸转运体阻滞剂的作用研究表明，喹啉酸是一种内源性兴奋毒素，与MCH神经元相比，它可能通过激活NMDA受体而导致增食欲素神经元的选择性丧失。此外，聚腺苷二磷酸-核糖聚合酶抑制剂可阻止喹啉酸引起的增食欲素神经元减少。这些结果为食欲素神经元的细胞毒性效应提供了第一个证据，并表明NMDA受体介导的损伤可能导致下丘脑这些神经元的选择性丢失，这是发作性睡病患者的一个显著的神经病理特征。(C)2003 Elsevier Inc.保留所有权利。
Several lines of evidence indicate that narcolepsy, a sleep disorder, results from the loss of hypothalamic orexin (hypocretin)-containing neurons, but the mechanisms responsible for selective elimination of this neuronal population are unknown. Using organotypic rat hypothalamic slice cultures, we investigated vulnerability of orexin neurons to excitotoxic insults. Twenty-four hours of incubation with N-methyl-D-aspartate (NMDA) followed by a recovery period of 72 h resulted in a marked decrease in the number of orexin-immunoreactive neurons, whereas melanin-concentrating hormone (MCH)-immunoreactive neurons in the same cultures were relatively spared. In contrast, orexin neurons were more resistant to kainic acid cytotoxicity than MCH neurons. Examinations of the effects of several endogenous glutamate receptor agonists as well as a glutamate transporter blocker highlighted quinolinic acid as an endogenous excitotoxin that could cause selective loss of orexin neurons as compared to MCH neurons by activating NMDA receptors. In addition, quinolinic acid-induced decrease of orexin neurons was prevented by an inhibitor of poly(ADP-ribose) polymerases. These results provide the first evidence concerning cytotoxic consequences onto orexin neurons, and indicate that NMDA receptor-mediated injury may contribute to the selective loss of these neurons in the hypothalamus, a prominent neuropathological feature found in narcolepsy patients. (C) 2003 Elsevier Inc. All rights reserved.