ATP-sensitive potassium-channel inhibitor glibenclamide attenuates HPA axis hyperactivity, depression- and anxiety-related symptoms in a rat model of Alzheimer's disease

• Published in: Brain research bulletin Vol. 137; pp. 265 - 276
• Main Authors: Esmaeili, Mohammad Hossein, Bahari, Behnam, Salari, Ali-Akbar
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.03.2018
• Subjects: Alzheimer disease; Alzheimer Disease - drug therapy; Alzheimer Disease - physiopathology; Alzheimer Disease - psychology; Amyloid beta-Peptides; Animals; Anxiety - drug therapy; Anxiety - physiopathology; ATP-sensitive potassium channel; Aβ25-35; Corticosterone - metabolism; Depression - drug therapy; Depression - physiopathology; Disease Models, Animal; Glibenclamide; Glyburide - pharmacology; HPA axis; Hypothalamo-Hypophyseal System - drug effects; Hypothalamo-Hypophyseal System - physiopathology; KATP Channels - antagonists & inhibitors; KATP Channels - metabolism; Nootropic Agents - pharmacology; Peptide Fragments; Pituitary-Adrenal System - drug effects; Pituitary-Adrenal System - physiopathology; Potassium Channel Blockers - pharmacology; Rats, Wistar; Stress, Psychological - drug therapy; Stress, Psychological - physiopathology; HPA axis; Glibenclamide; Alzheimer disease; Aβ25-35; ATP-sensitive potassium channel
• ISSN: 0361-9230; 1873-2747; 1873-2747
• DOI: 10.1016/j.brainresbull.2018.01.001

•Aβ25-35 microinjection induced anxiety- and depression-like behaviors in rats.•Aβ25-35 microinjection increased corticosterone and HPA axis activity in rats.•Glibenclamide decreased Aβ25-35-induced behavioral abnormalities in rats.•Glibenclamide reduced Aβ25-35-induced HPA axis hyperactivity in rats.•Glibenclamide, a KATP channel inhibitor, may be a therapeutic target for AD. 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-(KATP) 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 KATP 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, KATP 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 KATP 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 KATP channel inhibitors may be a plausible therapeutic strategy for treating affective disorders in AD patients.