Laboratory of Molecular Biology and Endocrinology, Institute of Nuclear Sciences "Vinča", University of Belgrade, 11001, Serbia.
Laboratory of Molecular Biology and Endocrinology, Institute of Nuclear Sciences "Vinča", University of Belgrade, 11001, Serbia.
Pharmacol Biochem Behav. 2017 Dec;163:57-65. doi: 10.1016/j.pbb.2017.10.006. Epub 2017 Oct 16.
Brain oxidative stress and neuroinflammation are implicated in psychiatric disorders. Thus, it is important to investigate the effects of individual psychotropic agents on antioxidative defense and proinflammatory mediators in brain regions associated with these disorders. Psychosocial stress is recognized as a threat to mental health, and the hippocampus is a primary target of stress-related damage. Chronic social isolation (CSIS) is a mild psychosocial stress used to model the pathophysiology of depression. We examined the antioxidative and anti-inflammatory potential of the antidepressant fluoxetine (FLX) and atypical antipsychotic clozapine (CLZ) in the hippocampus in the CSIS model of depression. We measured the effects of FLX and CLZ on depressive- and anxiety-like behaviors in non-stressed rats and rats exposed to 21d of CSIS. We further evaluated the content of reduced glutathione (GSH), the protein expression and activity of the GSH-related enzymes, the subcellular localization of nuclear factor-kappa B (NF-κB) and protein levels of proinflammatory mediators cyclooxygenase-2 (COX-2), interleukin-1beta (IL-1β), and tumor necrosis factor-alpha (TNF-α) in these groups of rats. CSIS resulted in an increase in depressive- and anxiety-like behaviors that corresponded with compromised glutathione peroxidase (GPx)-mediated antioxidative defense and increased TNF-α, but not with changes in NF-κB, IL-1β and COX-2 levels. FLX and CLZ, applied during CSIS, prevented the behavioral changes associated with CSIS, and inhibited the increase in TNF-α, but did not affect GPx-mediated antioxidative defense. Furthermore, both drugs decreased hippocampal GPx activity when applied to non-stressed rats. These results emphasize the significance of hippocampal TNF-α-mediated proinflammmatory signaling in the pathophysiology of depressive symptoms and the importance of the anti-inflammatory action of both FLX and CLZ in the prevention of these symptoms.
脑氧化应激和神经炎症与精神疾病有关。因此，研究个体精神药物对与这些疾病相关的脑区抗氧化防御和促炎介质的影响非常重要。心理社会应激被认为是心理健康的威胁，而海马体是应激相关损伤的主要靶标。慢性社会隔离（CSIS）是一种轻度的心理社会应激，用于模拟抑郁症的病理生理学。我们研究了抗抑郁药氟西汀（FLX）和非典型抗精神病药氯氮平（CLZ）在 CSIS 抑郁模型中海马体的抗氧化和抗炎潜力。我们测量了 FLX 和 CLZ 对非应激大鼠和暴露于 21d CSIS 的大鼠的抑郁样和焦虑样行为的影响。我们进一步评估了这些大鼠组中还原型谷胱甘肽（GSH）的含量、GSH 相关酶的蛋白表达和活性、核因子-κB（NF-κB）的亚细胞定位以及促炎介质环氧合酶-2（COX-2）、白细胞介素-1β（IL-1β）和肿瘤坏死因子-α（TNF-α）的蛋白水平。CSIS 导致抑郁样和焦虑样行为增加，与谷胱甘肽过氧化物酶（GPx）介导的抗氧化防御受损和 TNF-α增加有关，但与 NF-κB、IL-1β 和 COX-2 水平的变化无关。FLX 和 CLZ 在 CSIS 期间应用可预防与 CSIS 相关的行为变化，并抑制 TNF-α的增加，但不影响 GPx 介导的抗氧化防御。此外，两种药物在应用于非应激大鼠时均降低海马体 GPx 活性。这些结果强调了海马体 TNF-α 介导的促炎信号在抑郁症状病理生理学中的重要性，以及 FLX 和 CLZ 的抗炎作用在预防这些症状中的重要性。
