Abstract

Bipolar disorder (BD) is a multifactorial chronic and refractory disease characterized by manic, depressive, and mixed mood episodes. Although epidemiological, and pathophysiological studies demonstrated a strong correlation between bipolar disorder and oxidative stress, precise etiology is still missing. Recent studies suggested the possible role of transient receptor potential channels (TRP) in the BD but, current knowledge is limited. Therefore, the current study investigates the possible role of TRPV1 in the ouabain-induced model of BD. The model was created with intracerebroventricular single dose ouabain (10⁻³ M) administration. Animals were treated with capsaicin, capsazepine, and lithium for seven days. Mania and depressive-like states were investigated with open-field, sucrose preference, and elevated plus maze tests. Oxidative stress was assessed by measuring total antioxidant and oxidant states, spectrophotometrically. The phosphorylation Glycogen synthase kinase-3β (GSK-3β) evaluated by western blotting. Our results demonstrated that capsaicin dose-dependently inhibited the ouabain-induced hyperlocomotion and depression. Although capsazepine exacerbated behavioral impairment, it did not show a significant effect on the antioxidant and oxidant states, and the effects of capsazepine on behaviors were abolished by combination with capsaicin. Additionally, capsaicin potently prevented the ouabain-induced decrease in GSK-3β phosphorylation. In contrast, capsazepine potentiated ouabain-induced decrease in GSK-3β phosphorylation and combination with capsaicin, suppressed the effect of capsazepine on GSK-3β phosphorylation. The effects of TRPV1 activation on oxidative stress and mania-like behaviors in the ouabain-induced BD model might be regulated by GSK-3β phosphorylation.

摘要

双相情感障碍 (BD) 是一种多因素慢性难治性疾病，以躁狂、抑郁和混合情绪发作为特征。尽管流行病学和病理生理学研究表明双相情感障碍与氧化应激之间存在很强的相关性，但仍然缺少确切的病因。最近的研究表明瞬时受体电位通道 (TRP) 在 BD 中的可能作用，但目前的知识是有限的。因此，目前的研究调查了 TRPV1 在哇巴因诱导的 BD 模型中的可能作用。该模型是用脑室内单剂量哇巴因 (10 ^-3M) 管理。用辣椒素、capsazepine 和锂处理动物 7 天。通过开放场、蔗糖偏好和高架十字迷宫测试对躁狂和抑郁样状态进行了调查。通过分光光度法测量总抗氧化剂和氧化状态来评估氧化应激。通过蛋白质印迹评估磷酸化糖原合酶激酶-3β (GSK-3β)。我们的研究结果表明，辣椒素剂量依赖性地抑制哇巴因诱导的过度运动和抑郁。辣椒素虽然加剧了行为障碍，但对抗氧化和氧化状态没有显着影响，辣椒素对行为的影响被辣椒素消除。此外，辣椒素有效地阻止了哇巴因诱导的 GSK-3β 磷酸化降低。相比之下，capsazepine 可增强哇巴因诱导的 GSK-3β 磷酸化降低，并与辣椒素结合，抑制 capsazepine 对 GSK-3β 磷酸化的影响。TRPV1 激活对哇巴因诱导的 BD 模型中氧化应激和躁狂样行为的影响可能受 GSK-3β 磷酸化的调节。