Endothelin-A Receptor Antagonists Prevent Amyloid-β-Induced Increase in ET A Receptor Expression,Oxidative Stress,and Cognitive Impairment

Abstract

Alzheimer's disease is a neurodegenerative disorder associated with abnormal accumulation of amyloid-β (Aβ) which can release endothelin (ET). The present study was conducted to investigate the effect of ET antagonists on Aβ-induced changes in ET_A and ET_B receptor expression, oxidative stress, and cognitive impairment. Male Sprague-Dawley rats were treated with Aβ_1-40 in the lateral cerebral ventricles and were administered vehicle or ET antagonists for 14 days. Aβ treatment produced an increase in ET_A receptor expression in the cerebral cortex, hippocampus, and brain stem by 72%, 85%, and 90%, respectively. No change in ET_B receptor expression was observed. There was an increase in malondialdehyde (MDA) and decrease in reduced glutathione (GSH) and superoxide dismutase (SOD) levels in Aβ-treated rats. In the Morris swim task, Aβ treated rats showed a significant impairment in spatial memory. ET receptor antagonists, BQ123, BMS182874, and TAK-044, significantly decreased Aβ-induced increase in ET_A expression in the cortex, hippocampus, and brain stem. Rats treated with ET antagonists showed significant attenuation of Aβ-induced changes in the brain MDA, GSH, and SOD levels. Rats treated with specific ET_A receptor antagonists, BQ123 and BMS182874, significantly reduced the cognitive impairment induced by Aβ. However, nonspecific ET_A/ET_B receptor antagonist TAK-044 did not show any improvement in the learning and memory parameter. This study demonstrates that ET_A receptor antagonists are effective in preventing cognitive impairment, changes in ET_A expression and oxidative stress induced by Aβ. It is concluded that ET_A receptor antagonists may be useful in improving cognitive impairment due to Alzheimer's disease.