Laboratory of Molecular Biology and Endocrinology, Institute of Nuclear Sciences "Vinča", University of Belgrade, P. O. Box 522-090, 11001, Belgrade, Serbia.
J Neural Transm (Vienna). 2014 Jan;121(1):3-14. doi: 10.1007/s00702-013-1066-1. Epub 2013 Jul 14.
Stress-related glucocorticoids and glutamate release has been implicated in depression. Glutamate neurotoxicity is mediated, in part, by the production of nitric oxide via nitric oxide synthase (NOS) isoforms and mitochondrial damage. We previously reported that chronic social isolation stress triggers proapoptotic signaling in the rat prefrontal cortex, but not in the hippocampus. Given that the hippocampus is highly sensitive to stress, we examined signaling cascades underlying the hippocampal cellular protection through the NOS pathway, antioxidant capacity and heat shock protein (Hsp) expression. We investigated neuronal (nNOS) and inducible (iNOS) protein levels, subcellular protein distributions of nuclear factor-κB (NF-κB), CuZnSOD and MnSOD activity, reduced glutathione (GSH), stress-inducible Hsp70 (Hsp70i) protein expression and serum corticosterone (CORT) levels of rats exposed to 21 days of chronic social isolation, an animal model of depression, alone or in combination with 2 h of acute immobilization or cold stress (combined stress). Both acute stressors elevated CORT, with lesser magnitude increase in chronically isolated rats exposed to novel acute stress as compared to acute stressors alone, indicating compromised HPA axis activity. Acute cold decreased nuclear CuZnSOD activity and stimulated NF-κB nuclear translocation. Chronic social isolation resulted in no activation of NF-κB, but led to decreased GSH, iNOS and increased nNOS and Hsp70i levels, alterations that remained following combined stressors. Decreased mitochondrial MnSOD activity after combined stressors suggests compromised detoxifying capacity. These data indicate that Hsp70i upregulation may provide hippocampal cellular protection against chronic social isolation stress mediated by downregulation of iNOS protein expression through suppression of NF-κB activation.
应激相关的糖皮质激素和谷氨酸释放与抑郁症有关。谷氨酸神经毒性部分是通过一氧化氮合酶 (NOS) 同工型和线粒体损伤产生的一氧化氮介导的。我们之前的研究报告表明，慢性社交隔离应激会触发大鼠前额叶皮质的促凋亡信号，但不会触发海马体的促凋亡信号。鉴于海马体对压力高度敏感，我们通过 NOS 途径、抗氧化能力和热休克蛋白 (Hsp) 表达来研究海马体细胞保护的信号级联。我们研究了神经元 (nNOS) 和诱导型 (iNOS) 蛋白水平、核因子-κB (NF-κB)、CuZnSOD 和 MnSOD 活性、还原型谷胱甘肽 (GSH)、应激诱导的 Hsp70 (Hsp70i) 蛋白表达和血清皮质酮 (CORT) 水平在暴露于 21 天慢性社交隔离（一种抑郁症动物模型）、单独或与 2 小时急性束缚或冷应激（联合应激）的大鼠中的变化。两种急性应激源都会升高 CORT，而与单独急性应激源相比，慢性隔离大鼠在暴露于新的急性应激源时 CORT 升高幅度较小，表明 HPA 轴活性受损。急性冷应激会降低核 CuZnSOD 活性并刺激 NF-κB 核易位。慢性社交隔离不会导致 NF-κB 激活，但会导致 GSH 减少、iNOS 增加和 nNOS 和 Hsp70i 水平升高，这些变化在联合应激源后仍然存在。联合应激源后线粒体 MnSOD 活性降低表明解毒能力受损。这些数据表明，Hsp70i 的上调可能通过抑制 NF-κB 激活来下调 iNOS 蛋白表达，从而为海马体细胞提供对慢性社交隔离应激的保护。
