Peroxisomal proliferator-activated receptor (PPAR) is a number of a nuclear receptor superfamily and functions as a transcriptional regulator of genes linked to lipid metabolism. Recently, it was reported that PPARγ activated by 15-deoxy-Δ12,14 prostaglandin J2 (15d-PGJ2) and NSAIDs, inhibits inflammatory events such as induction of inducible nitric oxide synthase (iNOS) in monocytes /macrophages and glial cells. Also, it was recently reported that 15d-PGJ2 decreased the production of cyclooxygense-2 (COX-2) as well as iNOS production in LPS-stimulated BV-2 microglial cells. In this study, we have investigated effects of PPARα or PPARγ agonists in lipopolysaccharide (LPS)-induced neuronal cell death from mixed cortical neurons with glial cells in culture and the correlation with endogenous mediators of inflammation, such as COX-2 and iNOS expression. Interestingly, we found expression of iNOS was induced in microglia, but COX-2 was induced mostly in neurons of mixed cortical neurons by exposure of LPS. Neuronal death was assessed with MTT assay and TUNEL method. PPARγ agonists such as 15d-PGJ2 and ciglitazone, but not PPARα agonists such as clofibrate and Wy14643 prevented LPS-induced TUNEL positive neuronal death. PPARγ agonists, but not PPARα agonists abolished nitric oxide and prostaglandin E2(PGE2) production as well as COX-2 and iNOS expression induced by LPS. We showed the principal PPAR isoform in mixed cortical neurons was PPARγ but not PPARα, which demonstrated by using RT-PCR technique. PPARγ agonists suppressed LPS-induced COX-2 and iNOS expression interfering with NF-κB activation.
Taken together, we suggested that PPARγ agonists but not PPARα agonists prevented LPS-induced neuronal death which may be mediated by NO and PGE2. In addition, PPARγ agonists reduced LPS-induced iNOS and COX-2 expression in mixed cortical neurons with glial cells. These results might provided that neuroprotective effects of NSAID in neurodegenerative states associated with inflammation through activation of PPARγ receptor.
Source: Korean Journal of Physiology & Pharmacology.2000 Oct;4(Suppl):S18-S18
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