Maines M D, Eke B C, Weber C M, Ewing J F
Department of Biophysics, University of Rochester School of Medicine, New York.
J Neurochem. 1995 Apr;64(4):1769-79. doi: 10.1046/j.1471-4159.1995.64041769.x.
Activity of the stress protein, heme oxygenase-1 (hsp32; HO-1), produces carbon monoxide (CO), the potential messenger molecule for excitatory N-methyl-D-aspartate receptor-mediated events, in the hippocampus. Long-term stress caused by elevated adrenocorticoids induces pathological changes in CA1-CA3 neurons of the hippocampus; the adrenal hormones also exacerbate damage from stress. In rats chronically treated with corticosterone, we examined expression of HO-1 and its response to thermal stress in the hippocampus. An unprecedented appearance of scattered immunoreactive astrocytes marked the molecular layer of the hippocampus in corticosterone-treated rats. Steroid treatment showed no discernible effect on whole-brain HO-1 mRNA. When these rats were subjected to hyperthermia, neurons in the CA1-CA3 area, including pyramidal cells, exhibited intense immunoreactivity for the oxygenase and a pronounced increase (approximately 10-fold) in number. HO-1 is essentially undetectable in this area when rats are exposed to chronic corticosterone alone or thermal stress by itself, or in control rats. In contrast, similar analysis of hilar neurons showed no apparent effect on either the number or relative intensity of HO-1-immunostained cells after treatment. Corticosterone treatment also intensified the stress response of cerebellum, including Purkinje cells and Bergmann glia in the molecular layer. In brain, despite a pronounced reduction in NO synthase activity in corticosterone-treated and/or heat-stressed animals, the level of cyclic GMP was not significantly reduced. These observations are consistent with the hypothesis that responsiveness to environmental stress of CA1-CA3 neurons brought about by chronic elevation in circulating adrenocorticoids results in an increased excitatory neuronal activity and eventual hippocampal degeneration. Moreover, these findings yield further support for a role of CO in the production of cyclic GMP in the brain.
应激蛋白血红素加氧酶-1（热休克蛋白32；HO-1）的活性在海马体中产生一氧化碳（CO），这是兴奋性N-甲基-D-天冬氨酸受体介导事件的潜在信使分子。肾上腺皮质激素升高引起的长期应激会导致海马体CA1-CA3神经元发生病理变化；肾上腺激素也会加剧应激造成的损伤。在长期接受皮质酮治疗的大鼠中，我们检测了海马体中HO-1的表达及其对热应激的反应。在接受皮质酮治疗的大鼠中，海马体分子层出现了前所未有的散在免疫反应性星形胶质细胞。类固醇治疗对全脑HO-1 mRNA没有明显影响。当这些大鼠接受高温处理时，CA1-CA3区域的神经元，包括锥体细胞，对加氧酶表现出强烈的免疫反应性，数量明显增加（约10倍）。当大鼠单独暴露于慢性皮质酮或热应激本身时，或者在对照大鼠中，该区域基本检测不到HO-1。相比之下，对门区神经元的类似分析表明，治疗后HO-1免疫染色细胞的数量或相对强度没有明显影响。皮质酮治疗还增强了小脑的应激反应，包括浦肯野细胞和分子层的伯格曼胶质细胞。在大脑中，尽管在接受皮质酮治疗和/或热应激的动物中一氧化氮合酶活性明显降低，但环磷酸鸟苷水平并未显著降低。这些观察结果与以下假设一致：循环肾上腺皮质激素长期升高导致CA1-CA3神经元对环境应激的反应性增加，从而导致兴奋性神经元活动增加并最终导致海马体退化。此外，这些发现进一步支持了CO在大脑中环磷酸鸟苷产生中的作用。
