Activation of peroxisome proliferator-activated receptor-δ attenuates glutamate-induced neurotoxicity in HT22 mouse hippocampal cells

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)-d regulates glutamate-induced neurotoxicity in HT22 mouse hippocampal cells. Activation of PPARd 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 PPARd abrogated the effects of GW501516 in neuronal toxicity and ROS production induced by glutamate. In addition, ligand-activated PPARd reduced the glutamate-induced level of intracellular calcium ions (Ca2+) by modulating the influx of Ca2+ from the extracellular space. Similarly, glutamate-induced cell death and intracellular Ca2+ levels were attenuated in the presence of LY83583, an inhibitor of soluble guanylyl cyclase. Taken together, these results suggest that PPARd plays an important role in glutamate-induced neurotoxicity by modulating oxidative stress and Ca2+ influx. (c) 2012 Wiley Periodicals, Inc.