Zhao W, Tilton R G, Corbett J A, McDaniel M L, Misko T P, Williamson J R, Cross A H, Hickey W F
Department of Pathology, Dartmouth Medical School, Dartmouth-Hitchcock Medical Center, Lebanon, NH 03756 USA.
J Neuroimmunol. 1996 Feb;64(2):123-33. doi: 10.1016/0165-5728(95)00158-1.
This study assessed the role of de novo nitric oxide (NO) production in the pathogenesis of experimental allergic encephalomyelitis (EAE) by using aminoguanidine (AG), an inhibitor of nitric oxide synthase (NOS), which preferentially inhibits the cytokine- and endotoxin-inducible isoform of NOS versus the constitutive isoforms consisting of endothelial and neuronal NOS. The maximum clinical severity of EAE and the duration of illness were significantly reduced or totally inhibited by twice daily subcutaneous injection of 100 mg/kg body weight AG. Histochemical staining for NADPH diaphorase, which detects enzymatic activity of NOS, revealed positive reactivity in untreated EAE rats both in parenchymal blood vessel walls and in anterior horn cell neurons, while normal rats and rats with EAE treated with AG showed predominantly the neuronal positivity. Moreover, this NADPH staining pattern was further supported by the immunohistochemical findings that endothelial NOS (eNOS) expression was increased in blood vessels in the inflamed lesions of untreated EAE rats and that inducible NOS (iNOS) was detected in some inflammatory cells, while treatment with AG could significantly reduce both iNOS and eNOS production. These results suggest that: (i) both iNOS and eNOS are upregulated in inflamed areas of the rat central nervous system in EAE; (ii) increased NO production plays a role in the development of clinical signs in EAE; and (iii) selective inhibitors of iNOS and/or eNOS may have therapeutic potential for the treatment of certain autoimmune diseases.
本研究通过使用氨基胍（AG）评估了新生一氧化氮（NO）生成在实验性变态反应性脑脊髓炎（EAE）发病机制中的作用。AG是一种一氧化氮合酶（NOS）抑制剂，相对于由内皮型和神经元型NOS组成的组成型同工型，它优先抑制细胞因子和内毒素诱导的NOS同工型。通过每日两次皮下注射100mg/kg体重的AG，EAE的最大临床严重程度和病程显著降低或完全受到抑制。检测NOS酶活性的NADPH黄递酶组织化学染色显示，未经治疗的EAE大鼠的实质血管壁和前角细胞神经元均有阳性反应，而正常大鼠和接受AG治疗的EAE大鼠主要表现为神经元阳性。此外，这种NADPH染色模式得到了免疫组织化学结果的进一步支持，即未经治疗的EAE大鼠炎症病变血管中内皮型NOS（eNOS）表达增加，并且在一些炎症细胞中检测到诱导型NOS（iNOS），而AG治疗可显著降低iNOS和eNOS的生成。这些结果表明：（i）在EAE大鼠中枢神经系统的炎症区域，iNOS和eNOS均上调；（ii）NO生成增加在EAE临床症状的发展中起作用；（iii）iNOS和/或eNOS的选择性抑制剂可能对某些自身免疫性疾病具有治疗潜力。
