Activation of the peroxisome proliferator-activated receptor-alpha enhances cell death in cultured cerebellar granule cells.
Peroxisome proliferator-activated receptor-alpha (PPARalpha) is a member of the steroid hormone receptor superfamily. In rodents, PPARalpha alters genes involved in cell cycle regulation in hepatocytes. Some of these genes are implicated in neuronal cell death. Therefore, in this study, we examined the toxicological consequence of PPARalpha activation in rat primary cultures of cerebellar granule neurons. Our studies demonstrated the presence of PPARalpha mRNA in cultures by reverse transcriptase-polymerase chain reaction. After 10 days in vitro, cerebellar granule neuron cultures were incubated with the selective PPARalpha activator 4-chloro-6-(2,3-xylidino)2-pyrimidinylthioacetic acid (Wy-14,643). The inherent toxicity of Wy-14,643 and the effect of PPARalpha activation following toxic stimuli were assessed. In these studies, neurotoxicity was induced through reduction of extracellular [KCl] from 25 mM to 5.36 mM. We observed no inherent toxicity of Wy-14,643 (24 hr) in cultured cerebellar granule cells. However, after reduction of [KCl], cerebellar granule cell cultures incubated with Wy-14,643 showed significantly greater toxicity than controls. These results suggest a possible role for PPARalpha in augmentation of cerebellar granule neuronal death after toxic stimuli.
Smith
S A
SA
School of Pharmacy, The University of Queensland, St. Lucia, Queensland 4072, Australia.
May
F J
FJ
Monteith
G R
GR
Roberts-Thomson
S J
SJ
D000077556:Alitretinoin; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D002478:Cells, Cultured / Q000187:drug effects; D002525:Cerebellar Cortex / Q000166:cytology*; D007770:L-Lactate Dehydrogenase / Q000032:analysis; D009419:Nerve Tissue Proteins / Q000032:analysis / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology; D009474:Neurons / Q000187:drug effects*; D011189:Potassium Chloride / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology / Q000633:toxicity; D051381:Rats; D017207:Rats, Sprague-Dawley; D018160:Receptors, Cytoplasmic and Nuclear / Q000096:biosynthesis / Q000187:drug effects* / Q000235:genetics / Q000502:physiology; D018168:Receptors, Retinoic Acid / Q000819:agonists; D047488:Retinoid X Receptors; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014157:Transcription Factors / Q000819:agonists / Q000096:biosynthesis / Q000187:drug effects* / Q000235:genetics / Q000502:physiology; D014212:Tretinoin / Q000494:pharmacology; D015854:Up-Regulation / Q000187:drug effects
D009419:Nerve Tissue Proteins; D011743:Pyrimidines; D018160:Receptors, Cytoplasmic and Nuclear; D018168:Receptors, Retinoic Acid; D047488:Retinoid X Receptors; D014157:Transcription Factors; D000077556:Alitretinoin; D014212:Tretinoin; D011189:Potassium Chloride; C006253:pirinixic acid; D007770:L-Lactate Dehydrogenase