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Effects of peroxisome proliferator‐activated receptor γ ligands ciglitazone and 15‐deoxy‐Δ 12,14 ‐prostaglandin J 2 on rat cultured cerebellar granule neuronal viability
Author(s) -
Smith Steven A.,
Monteith Gregory R.,
Holman Nicola A.,
Robinson Jodie A.,
May Fiona J.,
RobertsThomson Sarah J.
Publication year - 2003
Publication title -
journal of neuroscience research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.72
H-Index - 160
eISSN - 1097-4547
pISSN - 0360-4012
DOI - 10.1002/jnr.10613
Subject(s) - ciglitazone , neuroprotection , neurotoxicity , peroxisome proliferator activated receptor , receptor , chemistry , pharmacology , biology , biochemistry , microbiology and biotechnology , toxicity , organic chemistry
Peroxisome proliferator‐activated receptor γ (PPARγ) has been the focus of studies assessing its potential neuroprotective role. These studies have shown either neuroprotection or neurotoxicity by PPARγ ligands. Comparison of these studies is complicated by the use of different PPARγ ligands, mechanisms of neurotoxicity induction, and neuronal cell type. In this study, we compared the effects of the synthetic PPARγ ligand ciglitazone with an endogenous PPARγ ligand, 15‐deoxy‐Δ 12,14 ‐prostaglandin J 2 (15‐deoxy PGJ 2 ), on inherent neurotoxicity and neuroprotection using a reduction in extracellular KCl in rat cultured cerebellar granule neurons (CGN). We also assessed the effects of these ligands on c‐Jun protein expression, which is up‐regulated on induction of low‐KCl‐mediated neuronal apoptosis as well as being associated with PPAR in other cell types. We showed that PPARγ mRNA is expressed in CGN cultures and observed ciglitazone‐ and 15‐deoxy PGJ 2 ‐mediated inherent neurotoxicity that was concentration and time dependent. c‐Jun was only modestly increased in the presence of ciglitazone but was markedly up‐regulated by 15‐deoxy PGJ 2 after 12 hr. Treatment of CGN cultures with ciglitazone simultaneous with KCl withdrawal resulted in a modest, time‐dependent neuroprotection. Such neuroprotection after KCl withdrawal was not observed with 15‐deoxy PGJ 2 . Despite the absence of neuroprotection, 15‐deoxy PGJ 2 markedly inhibited the early up‐regulation of c‐Jun during KCl withdrawal. These studies suggest that ciglitazone and 15‐deoxy PGJ 2 have markedly different effects on inherent and low‐KCl‐induced toxicity and c‐Jun expression in CGN, indicating potential non‐PPARγ mechanisms. © 2003 Wiley‐Liss, Inc.