Akasaka Soichiro, Nomura Masayoshi, Nishii Hisae, Fujimoto Naohiro, Ueta Yoichi, Tsutsui Masato, Shimokawa Hiroaki, Yanagihara Nobuyuki, Matsumoto Tetsuro
Department of Urology, School of Medicine, University of Occupational and Environmental Health, Kitakyushu 807-8555, Japan.
Brain Res. 2006 May 17;1089(1):1-9. doi: 10.1016/j.brainres.2006.02.112. Epub 2006 May 2.
Nitric oxide (NO) generated by inducible NO synthase (iNOS) may be implicated in the biological responses of the central nervous system to immune stimuli. To elucidate the role of iNOS in the hypothalamo-pituitary axis in responses to endotoxemia, using iNOS knockout (KO) mice, we examined the levels of c-fos, a neural activational marker, and corticotropin-releasing hormone (CRH) gene transcription in the paraventricular nucleus (PVN) and central amygdala (CeAMY) during lipopolysaccharide (LPS)-induced endotoxemia. In addition, the serum adrenocorticotropic hormone (ACTH) levels were also examined during endotoxemia. Following the intraperitoneal administration of LPS (1 mg/kg), the levels of the c-fos gene expression significantly increased in the PVN and the CeAMY regardless of the genotype. However, the disruption of the iNOS gene resulted in a significant decrease in the c-fos gene induction in the PVN in comparison to that observed in control mice. LPS administration caused a significant increase in CRH mRNA levels in the PVN and CeAMY regardless of genotype. However, the LPS-induced upregulation of CRH mRNA was significantly attenuated in the PVN of iNOS KO mice in comparison to that in the control mice. In contrast, no such genotype differences in the neural activity or CRH gene transcription were observed in the CeAMY. The serum ACTH responses to LPS were also significantly blunted in the iNOS KO mice in comparison to the control mice. These results suggest that iNOS-derived NO may therefore play a stimulatory role in the activity of the hypothalamo-pituitary axis during endotoxemia.
诱导型一氧化氮合酶（iNOS）产生的一氧化氮（NO）可能参与中枢神经系统对免疫刺激的生物学反应。为了阐明iNOS在下丘脑-垂体轴对内毒素血症反应中的作用，我们使用iNOS基因敲除（KO）小鼠，检测了脂多糖（LPS）诱导的内毒素血症期间，室旁核（PVN）和中央杏仁核（CeAMY）中神经激活标记物c-fos的水平以及促肾上腺皮质激素释放激素（CRH）基因转录情况。此外，还检测了内毒素血症期间血清促肾上腺皮质激素（ACTH）水平。腹腔注射LPS（1 mg/kg）后，PVN和CeAMY中c-fos基因表达水平均显著升高，与基因型无关。然而，与对照小鼠相比，iNOS基因的缺失导致PVN中c-fos基因诱导显著减少。LPS给药导致PVN和CeAMY中CRH mRNA水平显著升高，与基因型无关。然而，与对照小鼠相比，iNOS KO小鼠PVN中LPS诱导的CRH mRNA上调显著减弱。相比之下，CeAMY中未观察到神经活动或CRH基因转录的基因型差异。与对照小鼠相比，iNOS KO小鼠对LPS的血清ACTH反应也显著减弱。这些结果表明，内毒素血症期间，iNOS衍生的NO可能在下丘脑-垂体轴的活动中起刺激作用。
