Pichili V B R, Rao K V Rama, Jayakumar A R, Norenberg M D
Department of Pathology, University of Miami School of Medicine, Miami, Florida 33101, USA.
Glia. 2007 Jun;55(8):801-9. doi: 10.1002/glia.20499.
Hepatic encephalopathy (HE) is a major neurological complication that occurs in the setting of severe liver failure. Ammonia is a key neurotoxin implicated in this condition, and astrocytes are the principal neural cells histopathologically and functionally affected. Although the mechanism by which ammonia causes astrocyte dysfunction is incompletely understood, glutamine, a by-product of ammonia metabolism, has been strongly implicated in many of the deleterious effects of ammonia on astrocytes. Inhibiting mitochondrial glutamine hydrolysis in astrocytes mitigates many of the toxic effects of ammonia, suggesting the involvement of mitochondrial glutamine metabolism in the mechanism of ammonia neurotoxicity. To determine whether mitochondriaare indeed the organelle where glutamine exerts its toxic effects, we examined the effect of L-histidine, an inhibitor of mitochondrial glutamine transport, on ammonia-mediated astrocyte defects. Treatment of cultured astrocytes with L-histidine completely blocked or significantly attenuated ammonia-induced reactive oxygen species production, cell swelling, mitochondrial permeability transition, and loss of ATP. These findings implicate mitochondrial glutamine transport in the mechanism of ammonia neurotoxicity.
肝性脑病（HE）是严重肝功能衰竭时发生的一种主要神经并发症。氨是与此病症相关的一种关键神经毒素，星形胶质细胞是在组织病理学和功能上受到影响的主要神经细胞。尽管氨导致星形胶质细胞功能障碍的机制尚未完全明确，但氨代谢的副产物谷氨酰胺在氨对星形胶质细胞的许多有害作用中起到了重要作用。抑制星形胶质细胞中的线粒体谷氨酰胺水解可减轻氨的许多毒性作用，这表明线粒体谷氨酰胺代谢参与了氨神经毒性机制。为了确定线粒体是否确实是谷氨酰胺发挥其毒性作用的细胞器，我们研究了线粒体谷氨酰胺转运抑制剂L-组氨酸对氨介导的星形胶质细胞缺陷的影响。用L-组氨酸处理培养的星形胶质细胞可完全阻断或显著减轻氨诱导的活性氧生成、细胞肿胀、线粒体通透性转换和ATP丧失。这些发现表明线粒体谷氨酰胺转运参与了氨神经毒性机制。
