Peroxisome proliferator-activated receptor gamma activation decreases neuroinflammation in brain after stress in rats
Peroxisome proliferator-activated receptor gamma activation decreases neuroinflammation in brain after stress in rats
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DOI：
10.1016/j.biopsych.2005.01.007
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发表时间：
2005-04-15
影响因子：
10.6
通讯作者：
Leza, JC
中科院分区：
文献类型：
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作者：
García-Bueno, B;Madrigal, JLM;Leza, JC
背景资料：越来越多的证据表明，过氧化物酶体增殖物激活受体γ（PPAR γ）在脑炎症中发挥作用，因为各种PPAR γ配体抑制促炎介质，如细胞因子（肿瘤坏死因子α [TNF α]）和诱导型一氧化氮合酶（NOS-2）。如前所述，制动应激和应激相关的神经心理学状况之后，在脑中释放细胞因子、核因子κ B活化以及NOS-2和环氧合酶2（考克斯-2）表达之后，氧化/亚硝化介质在脑中积累。为了评估过氧化物酶体增殖物激活受体γ激活是否可以改变应激后脑中氧化/亚硝化物质的积累，并研究这种作用的机制，在应激开始时向成年雄性Wistar大鼠（对照组和固定6小时）注射高亲和力配体罗格列酮（RS）。通过Western印迹和免疫组织化学评估，应激增加了皮质神经元和神经胶质细胞中的PPAR γ表达。在应激动物中，RS（1-3 mg/kg）降低了应激诱导的NOS-2活性增加。另一方面，过氧化物酶体增殖物激活受体γ配体减少了应激诱导的丙二醛（脂质过氧化反应的一个指标）在皮层的积累，并防止氧化的主要抗氧化剂谷胱甘肽。应激时RS抗氧化特性的机制涉及核因子κ B阻断（通过防止应激诱导的I κ B α降低）和抑制应激动物中TNF α的释放。在测试的剂量下，RS在应激期间没有降低考克斯-2表达和前列腺素E2释放。最后，RS还降低慢性（重复制动21天）应激诱导的氧化/亚硝化介质的积累。两者合计，这些研究结果表明，这一信号通路的作用，在大脑的应激反应和药理学调制的可能性，以防止积累的氧化/亚硝化物种和随后的脑损伤，在应激相关的神经心理条件。
Background: A growing body of evidence has demonstrated that peroxisome proliferator-activated receptor gamma (PPAR gamma) play a role in brain inflammatory conditions because various PPAR gamma ligands inhibit proinflammatory mediators, such as cytokines (tumor necrosis factor alpha [TNF alpha]) and inducible nitric oxide synthase (NOS-2). As has been previously shown, immobilization stress and stress-related neuropsychologic conditions are followed by accumulation of oxidative/nitrosative mediators in brain after the release of cytokines, nuclear factor kappa B activation, and NOS-2 and cyclooxygenase 2 (COX-2) expression in the brain.Methods. To assess whether PPAR gamma activation can modify the accumulation of oxidative/nitrosative species seen in brain after stress, and to study the mechanisms by which this effect is achieved, young-adult male Wistar rats (control and immobilized during 6 hours) were injected (IP) with the high-affinity ligand rosiglitazone (RS) at the onset of stress.Results. Stress increased PPAR gamma expression in cortical neurons and glia as assessed by Western blot and immunohistochemistry. In stressed animals, RS (1-3 mg/kg,) decreased stress-induced increases in NOS-2 activity. On the other band, the PPAR gamma ligand decreased stress-induced malondialdehyde (an indicator of lipid peroxidation) accumulation in cortex and prevented oxidation of the main antioxidant glutathione. The mechanisms involved in the antioxidative properties of RS in stress involve nuclear factor kappa B blockade (by preventing stress-induced I kappa B alpha decrease) and inhibition of TNF alpha release in stressed animals. At the doses tested, RS did not decrease COX-2 expression and prostaglandin E2 release during stress. Finally, RS also decreased chronic (repeated immobilization for 21 days) stress-induced accumulation of oxidative/nitrosative mediators.Conclusions. Taken together, these findings suggest a role for this antiinflammatory pathway in the brain response to stress and the possibility of pharmacologic modulation for preventing accumulation of oxidative/nitrosative species and subsequent brain damage in stress-related neuropsychologic conditions.