Chen Jing, Qin Jiong, Liu Xiaoyan, Han Ying, Yang Zhixian, Chang Xingzhi, Ji Xinna
Department of Pediatrics, Peking University First Hospital, Beijing 100034, People's Republic of China.
Neurosci Lett. 2008 Oct 10;443(3):134-9. doi: 10.1016/j.neulet.2008.07.060. Epub 2008 Jul 26.
Nitric oxide (NO), as a neurotransmitter, exerts various physiological and pathological effects on the brain. Excess NO is toxic to neurons and may cause neuronal apoptosis. However, the cascade of NO-mediated apoptosis is not fully understood. We utilized a recurrent febrile seizures (FS) rat model and found that plasma NO was increased, neuronal apoptosis was evident, the expression of glucose-regulated protein78 (GRP78, a well-established marker of ER stress) was elevated, and caspase-12 (an ER stress-specific proapoptosis molecule) was activated in the hippocampus in a time-dependent manner after recurrent FS. Administration of sodium nitroprusside (SNP, an NO donor) enhanced neuronal apoptosis, down-regulated the expression of GRP78, and increased that of caspase-12 in FS+SNP groups compared with FS groups. In contrast, treatment with N(G)-nitrol-l-arginine methyl ester (l-NAME, a competitive NO synthase inhibitor) inhibited neuronal apoptosis, up-regulated the expression of GRP78, and decreased that of caspase-12 in FS+l-NAME groups compared with FS groups. These results suggest that NO mediates neuronal apoptosis caused by recurrent FS, and that the ER stress pathway is involved in NO-mediated neuronal apoptosis.
一氧化氮（NO）作为一种神经递质，对大脑具有多种生理和病理作用。过量的NO对神经元有毒性，可能导致神经元凋亡。然而，NO介导的细胞凋亡级联反应尚未完全明确。我们利用反复发热惊厥（FS）大鼠模型，发现反复FS后，血浆NO升高，神经元凋亡明显，葡萄糖调节蛋白78（GRP78，一种公认的内质网应激标志物）的表达升高，并且半胱天冬酶-12（一种内质网应激特异性促凋亡分子）在海马中呈时间依赖性激活。与FS组相比，在FS+硝普钠（SNP，一种NO供体）组中，给予硝普钠可增强神经元凋亡，下调GRP78的表达，并增加半胱天冬酶-12的表达。相反，与FS组相比，在FS+N（G）-硝基-L-精氨酸甲酯（L-NAME，一种竞争性NO合酶抑制剂）组中，用L-NAME治疗可抑制神经元凋亡，上调GRP78的表达，并降低半胱天冬酶-12的表达。这些结果表明，NO介导反复FS引起的神经元凋亡，并且内质网应激途径参与了NO介导的神经元凋亡。
