Izumi Yukitoshi, Izumi Masayo, Matsukawa Mio, Funatsu Michiyo, Zorumski Charles F
Department of Psychiatry, Washington University School of Medicine, 660 S Euclid Avenue, St. Louis, MO 63110, USA.
Neurobiol Dis. 2005 Nov;20(2):615-24. doi: 10.1016/j.nbd.2005.04.013. Epub 2005 Jun 1.
Because hyperammonemia is thought to contribute to the pathogenesis of hepatic encephalopathy, we examined the effects of ammonia on ATP levels, neuronal morphology, and synaptic function in rat hippocampal slices. Although ammonia did not alter ATP levels supported by 10 mM glucose, ammonia significantly depressed ATP levels in the presence of 3.3 mM glucose or 10 mM pyruvate, suggesting effects on respiratory energy metabolism. Ammonia also impaired synaptic function and neuronal integrity sustained by pyruvate. In 10 mM glucose, ammonia inhibited the induction and maintenance of long-term potentiation (LTP) in a concentration-dependent fashion. These inhibitory effects of ammonia were overcome by L-carnitine. DL-APV, an antagonist of NMDA receptors, also diminished the effects of ammonia on ATP levels and LTP induction, indicating that ammonia impairs neuronal function via altered metabolism and untimely NMDA receptor activation. These results suggest that L-carnitine and NMDA receptor antagonists have the potential to preserve neuronal function during hyperammonemia.
由于高氨血症被认为与肝性脑病的发病机制有关，我们研究了氨对大鼠海马切片中ATP水平、神经元形态和突触功能的影响。尽管氨不会改变由10 mM葡萄糖支持的ATP水平，但在存在3.3 mM葡萄糖或10 mM丙酮酸的情况下，氨会显著降低ATP水平，提示其对呼吸能量代谢有影响。氨还损害了由丙酮酸维持的突触功能和神经元完整性。在10 mM葡萄糖中，氨以浓度依赖性方式抑制长时程增强（LTP）的诱导和维持。L-肉碱可克服氨的这些抑制作用。NMDA受体拮抗剂DL-APV也减弱了氨对ATP水平和LTP诱导的影响，表明氨通过改变代谢和过早激活NMDA受体来损害神经元功能。这些结果表明，L-肉碱和NMDA受体拮抗剂有可能在高氨血症期间保护神经元功能。
