Effect of the peroxisome proliferator-activated receptor beta activator GW0742 in rat cultured cerebellar granule neurons.
The ligand-activated transcription factor peroxisome proliferator-activated receptor beta (PPARbeta) 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 PPARbeta in neuronal cell death by using the PPARbeta 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 PPARbeta 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, PPARbeta 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 PPARalpha-activating ligands, PPARbeta 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 PPARbeta is worthy of further investigation regarding its potential role as a therapeutic target in neurodegenerative states.
Smith
Steven A
SA
School of Pharmacy, The University of Queensland, St. Lucia, Queensland, Australia.
Monteith
Gregory R
GR
Robinson
Jodie A
JA
Venkata
Nagaraj Gopisetty
NG
May
Fiona J
FJ
Roberts-Thomson
Sarah J
SJ
D000818:Animals; D000831:Animals, Newborn; D016923:Cell Death / Q000187:drug effects / Q000502:physiology*; D002478:Cells, Cultured; D002531:Cerebellum / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D007770:L-Lactate Dehydrogenase / Q000187:drug effects / Q000378:metabolism; D009410:Nerve Degeneration / Q000139:chemically induced / Q000378:metabolism*; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D009498:Neurotoxins / Q000037:antagonists & inhibitors / Q000378:metabolism; D011191:Potassium Deficiency / Q000378:metabolism; D016755:Proto-Oncogene Proteins c-jun / Q000187:drug effects / Q000378:metabolism; D011743:Pyrimidines / Q000494:pharmacology; D012333:RNA, Messenger / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists / Q000235:genetics / Q000378:metabolism*; D013844:Thiazoles / Q000494:pharmacology*; D014157:Transcription Factors / Q000819:agonists / Q000235:genetics / Q000378:metabolism*; D010636:Phenols; D013438:Sulfhydryl Compounds
D007770:L-Lactate Dehydrogenase; D009498:Neurotoxins; D016755:Proto-Oncogene Proteins c-jun; D011743:Pyrimidines; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; D013844:Thiazoles; D014157:Transcription Factors; C479979:(4-(((2-(3-fluoro-4-(trifluoromethyl)phenyl)-4-methyl-1,3-thiazol-5-yl)methyl)sulfanyl)-2-methylphenoxy)acetic acid; D010636:Phenols; D013438:Sulfhydryl Compounds; C006253:pirinixic acid