Effect of the peroxisome proliferator-activated receptor β activator GW0742 in rat cultured cerebellar granule neurons

Abstract

The ligand-activated transcription factor peroxisome proliferator-activated receptor β (PPARβ) is present in the brain and is implicated in the regulation of genes with potential roles in neurotoxicity. We sought to examine the role of PPARβ in neuronal cell death by using the PPARβ ligand GW0742. Primary cultures of rat cerebellar granule neurons were prepared from 7-day-old pups. Reverse transcriptase-polymerase chain reaction and in situ hybridization were used to verify that PPARβ mRNA was present in neurons. After 10-12 days in culture, the neuronal cells were incubated in the presence of GW0742, and cell death was measured with a lactate dehydrogenase release (LDH) assay. After 24 hr of exposure, PPARβ activation by GW0742 was not inherently toxic to cerebellar granule neurons. However, toxicity was observed after 48 hr, with cell death mediated via an apoptotic mechanism. In an effect opposite to that observed with PPARβ-activating ligands, PPARβ activation exhibited neuroprotective properties. Treatment with GW0742 significantly reduced cell death during a 12-hr exposure to low-KCl media. These results clearly reinforce very specific roles for the PPAR isoforms in neurons and suggest that PPARβ is worthy of further investigation regarding its potential role as a therapeutic target in neurodegenerative states. © 2004 Wiley-Liss, Inc.