Department of Pharmacology, Gyeongsang National University School of Medicine, Jinju, Korea.
J Neurosci Res. 2012 Aug;90(8):1646-53. doi: 10.1002/jnr.23053. Epub 2012 Mar 31.
Glutamate-induced neurotoxicity has been implicated in the pathogenesis of neurodegenerative disorders; however, little is known about the cellular events that underlie neurotoxicity or how to impede these events. This study demonstrates that peroxisome proliferator-activated receptor (PPAR)-δ regulates glutamate-induced neurotoxicity in HT22 mouse hippocampal cells. Activation of PPARδ by GW501516, a specific ligand, significantly inhibited glutamate-induced cell death and reactive oxygen species (ROS) production in HT22 cells. The siRNA-mediated knockdown of PPARδ abrogated the effects of GW501516 in neuronal toxicity and ROS production induced by glutamate. In addition, ligand-activated PPARδ reduced the glutamate-induced level of intracellular calcium ions (Ca(2+)) by modulating the influx of Ca(2+) from the extracellular space. Similarly, glutamate-induced cell death and intracellular Ca(2+) levels were attenuated in the presence of LY83583, an inhibitor of soluble guanylyl cyclase. Taken together, these results suggest that PPARδ plays an important role in glutamate-induced neurotoxicity by modulating oxidative stress and Ca(2+) influx.
谷氨酸诱导的神经毒性与神经退行性疾病的发病机制有关；然而，对于导致神经毒性的细胞事件以及如何阻止这些事件知之甚少。本研究表明过氧化物酶体增殖物激活受体 (PPAR)-δ 调节 HT22 小鼠海马细胞中的谷氨酸诱导的神经毒性。特异性配体 GW501516 激活 PPARδ 可显著抑制 HT22 细胞中谷氨酸诱导的细胞死亡和活性氧 (ROS) 产生。siRNA 介导的 PPARδ 敲低消除了 GW501516 在谷氨酸诱导的神经元毒性和 ROS 产生中的作用。此外，配体激活的 PPARδ 通过调节细胞外 Ca(2+) 内流来降低谷氨酸诱导的细胞内钙离子 (Ca(2+)) 水平。同样，在存在可溶性鸟苷酸环化酶抑制剂 LY83583 的情况下，谷氨酸诱导的细胞死亡和细胞内 Ca(2+) 水平降低。综上所述，这些结果表明 PPARδ 通过调节氧化应激和 Ca(2+) 内流在谷氨酸诱导的神经毒性中发挥重要作用。
