Cellular and Molecular Research Center & Department of Physiology, Qazvin University of Medical Sciences, Qazvin, Iran.
Drug Applied Research Center, Tabriz University of Medical Sciences, Tabriz, Iran; Salari Institute of Cognitive and Behavioral Disorders (SICBD), Alborz, Iran.
Brain Res Bull. 2018 Mar;137:265-276. doi: 10.1016/j.brainresbull.2018.01.001. Epub 2018 Jan 4.
Affective disorders including depression and anxiety are among the most prevalent behavioral abnormalities in patients with Alzheimer's disease (AD), which affect the quality of life and progression of the disease. Dysregulation of the hypothalamic-pituitary-adrenal-(HPA) axis has been reported in affective disorders and AD. Recent studies revealed that current antidepressant drugs are not completely effective for treating anxiety- and depression-related disorders in people with dementia. ATP-sensitive-potassium-(K) channels are well-known to be involved in AD pathophysiology, HPA axis function and the pathogenesis of depression and anxiety-related behaviors. Thus, targeting of K channel may be a potential therapeutic strategy in AD. Hence, we investigated the effects of intracerebroventricular injection of Aβ25-35 alone or in combination with glibenclamide, K channel inhibitor on depression- and anxiety-related behaviors as well as HPA axis response to stress in rats. To do this, non-Aβ25-35- and Aβ25-35-treated rats were orally treated with glibenclamide, then the behavioral consequences were assessed using sucrose preference, forced swim, light-dark box and plus maze tests. Stress-induced corticosterone levels following forced swim and plus maze tests were also evaluated as indicative of abnormal HPA-axis-function. Aβ25-35 induced HPA axis hyperreactivity and increased depression- and anxiety-related symptoms in rats. Our results showed that blockade of K channels with glibenclamide decreased depression- and anxiety-related behaviors by normalizing HPA axis activity in Aβ25-35-treated rats. This study provides additional evidence that Aβ administration can induce depression- and anxiety-like symptoms in rodents, and suggests that K channel inhibitors may be a plausible therapeutic strategy for treating affective disorders in AD patients.
情感障碍包括抑郁症和焦虑症，是阿尔茨海默病（AD）患者最常见的行为异常之一，会影响患者的生活质量和疾病进展。情感障碍和 AD 中均报道了下丘脑-垂体-肾上腺（HPA）轴的失调。最近的研究表明，目前的抗抑郁药对于治疗痴呆患者的焦虑和抑郁相关障碍并不完全有效。三磷酸腺苷敏感性钾（K）通道众所周知与 AD 病理生理学、HPA 轴功能以及抑郁和焦虑相关行为的发病机制有关。因此，靶向 K 通道可能是 AD 的一种潜在治疗策略。因此，我们研究了单独或联合给予 Aβ25-35 以及给予 K 通道抑制剂格列本脲对大鼠的抑郁和焦虑相关行为以及 HPA 轴对压力的反应的影响。为此，我们用 Aβ25-35 处理大鼠，并给予格列本脲口服治疗，然后使用蔗糖偏好、强迫游泳、明暗箱和十字迷宫测试评估行为后果。还评估了强迫游泳和十字迷宫测试后应激诱导的皮质酮水平，作为 HPA 轴功能异常的指标。Aβ25-35 诱导 HPA 轴反应过度，并增加了大鼠的抑郁和焦虑相关症状。我们的结果表明，用格列本脲阻断 K 通道可通过使 Aβ25-35 处理的大鼠的 HPA 轴活性正常化来减少抑郁和焦虑相关行为。这项研究提供了更多的证据表明，Aβ 给药可以在啮齿动物中引起抑郁和焦虑样症状，并表明 K 通道抑制剂可能是治疗 AD 患者情感障碍的合理治疗策略。
