Llansola Marta, Rodrigo Regina, Monfort Pilar, Montoliu Carmina, Kosenko Elena, Cauli Omar, Piedrafita Blanca, El Mlili Nisrin, Felipo Vicente
Laboratory of Neurobiology, Centro de Investigacion Principe Felipe, Fundación de la Comunidad Valenciana Centro de Investigacion Principe Felipe, Avda Autopista del Saler, 16, 46013, Valencia, Spain.
Metab Brain Dis. 2007 Dec;22(3-4):321-35. doi: 10.1007/s11011-007-9067-0.
The NMDA type of glutamate receptors modulates learning and memory. Excessive activation of NMDA receptors leads to neuronal degeneration and death. Hyperammonemia and liver failure alter the function of NMDA receptors and of some associated signal transduction pathways. The alterations are different in acute and chronic hyperammonemia and liver failure. Acute intoxication with large doses of ammonia (and probably acute liver failure) leads to excessive NMDA receptors activation, which is responsible for ammonia-induced death. In contrast, chronic hyperammonemia induces adaptive responses resulting in impairment of signal transduction associated to NMDA receptors. The function of the glutamate-nitric oxide-cGMP pathway is impaired in brain in vivo in animal models of chronic liver failure or hyperammonemia and in homogenates from brains of patients died in hepatic encephalopathy. The impairment of this pathway leads to reduced cGMP and contributes to impaired cognitive function in hepatic encephalopathy. Learning ability is reduced in animal models of chronic liver failure and hyperammonemia and is restored by pharmacological manipulation of brain cGMP by administering phosphodiesterase inhibitors (zaprinast or sildenafil) or cGMP itself. NMDA receptors are therefore involved both in death induced by acute ammonia toxicity (and likely by acute liver failure) and in cognitive impairment in hepatic encephalopathy.
N-甲基-D-天冬氨酸(NMDA)型谷氨酸受体调节学习和记忆。NMDA受体的过度激活会导致神经元变性和死亡。高氨血症和肝功能衰竭会改变NMDA受体以及一些相关信号转导通路的功能。急性和慢性高氨血症及肝功能衰竭时的改变有所不同。大剂量氨急性中毒(可能还有急性肝功能衰竭)会导致NMDA受体过度激活,这是氨诱导死亡的原因。相反,慢性高氨血症会诱导适应性反应,导致与NMDA受体相关的信号转导受损。在慢性肝功能衰竭或高氨血症动物模型的体内大脑以及死于肝性脑病患者的脑匀浆中,谷氨酸-一氧化氮-环磷酸鸟苷(cGMP)通路的功能受损。该通路的受损导致cGMP减少,并促成肝性脑病中的认知功能障碍。在慢性肝功能衰竭和高氨血症动物模型中学习能力降低,通过给予磷酸二酯酶抑制剂(扎普司特或西地那非)或cGMP本身对脑cGMP进行药理学调控可恢复学习能力。因此,NMDA受体既参与急性氨中毒(可能还有急性肝功能衰竭)诱导的死亡,也参与肝性脑病中的认知障碍。