Peroxisome Proliferator-activated Receptor (PPAR)-γ Modifies Aβ Neurotoxin-induced Electrophysiological Alterations in Rat Primary Cultured Hippocampal Neurons

Document Type: Research article

Authors

1 Neuroscience Research Center, Department of Physiology, Faculty of Medicine, Baqiyatallah University of Medical Sciences, Tehran, Iran.

2 Neuroscience Research Center, Department of Physiology, School of Medical, Shahid Beheshti University of Medical Sciences, Tehran, Iran.

Abstract

Alzheimer’s disease (AD) is undoubtedly one of the serious and growing public health challenges in the world today. There is an unmet need for new and effective preventative and therapeutic treatment approaches for AD, particularly at early stages of the disease. However, the underlying mechanism against Aβ-induced electrophysiological alteration in cultured hippocampal pyramidal neurons  is still not fully understood. This study investigated  the impacts of activation and inhibition of PPAR-γ/δ on the Aβ-induced functional toxicity, which occured before cell death, using patch clamp technique. Findings demonstrated that Aβ treatment alone altered the normal electrophysiological properties and reduced the Ca2+ channel currents in primary cultured hippocampal pyramidal neurons without any major changes either in cell structure, as evidenced by electron microscope examination, or cell viability. Rosiglitazone (30 μM), a potent PPAR-γ activator, when co-treated with Aβ (100 nM) prevented almost completely the induction of function toxicity of Aβ, as evidentiated by restored normal appearing electrophysiological properties. Inhibition of PPAR- γ/δ by FH535 (15 μM), an inhibitor of both Wnt/beta-catenin signaling and PPAR- γ and δ activity, when applied in combination of Aβ not only worsen the toxic electrophysiological effects of Aβ on firing frequency, membrane resistance and cell viability, but also even preserved the suppressive effect of Aβ on Ca2+ channel current when compared to control condition. Overall, these findings suggest that PPAR-γ activation could be a potential candidate to prevent the functional changes induced by low concentration of Aβ which may possibly occur in neurons during early stages of AD.

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Iranian Journal of Pharmaceutical Research

Volume 18, Issue 3
Summer 2019
Pages 1403-1418

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