Bahrami Farideh, Asgari Alireza, Hosseinmardi Narges, Janahmadi Mahyar
Neuroscience Research Center, Department of Physiology, Faculty of Medicine, Baqiyatallah University of Medical Sciences, Tehran, Iran.
Neuroscience Research Center, Department of Physiology, School of Medical, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
Iran J Pharm Res. 2019 Summer;18(3):1403-1418. doi: 10.22037/ijpr.2019.1100783.
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 Ca 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 Ca 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.
阿尔茨海默病（AD）无疑是当今世界严重且日益严峻的公共卫生挑战之一。对于AD，尤其是在疾病早期，迫切需要新的、有效的预防和治疗方法。然而，针对培养的海马锥体神经元中Aβ诱导的电生理改变的潜在机制仍未完全明确。本研究采用膜片钳技术，研究了PPAR-γ/δ的激活和抑制对Aβ诱导的、在细胞死亡之前发生的功能毒性的影响。研究结果表明，单独使用Aβ处理会改变原代培养海马锥体神经元的正常电生理特性，并降低钙通道电流，而电子显微镜检查显示细胞结构无任何重大变化，细胞活力也无变化。罗格列酮（30 μM）是一种有效的PPAR-γ激活剂，与Aβ（100 nM）共同处理时，几乎完全防止了Aβ功能毒性的诱导，恢复正常的电生理特性即可证明。FH535（15 μM）是Wnt/β-连环蛋白信号传导以及PPAR-γ和δ活性的抑制剂，与Aβ联合应用时，不仅会使Aβ对放电频率、膜电阻和细胞活力的毒性电生理效应恶化，而且与对照条件相比，甚至会保留Aβ对钙通道电流的抑制作用。总体而言，这些发现表明，PPAR-γ激活可能是预防低浓度Aβ诱导的功能变化的潜在候选方法，这种变化可能在AD早期的神经元中发生。
