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Gemfibrozil, a Lipid Lowering Drug, Inhibits the Activation of Primary Human Microglia Via Peroxisome Proliferator-Activated Receptor β

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Abstract

Microglial activation participates in the pathogenesis of various neuroinflammatory and neurodegenerative diseases. However, mechanisms by which microglial activation could be controlled are poorly understood. Peroxisome proliferator-activated receptors (PPAR) are transcription factors belonging to the nuclear receptor super family with diverse effect. This study underlines the importance of PPARβ/δ in mediating the anti-inflammatory effect of gemfibrozil, an FDA-approved lipid-lowering drug, in primary human microglia. Bacterial lipopolysachharides (LPS) induced the expression of various proinflammatory molecules and upregulated the expression of microglial surface marker CD11b in human microglia. However, gemfibrozil markedly suppressed proinflammatory molecules and CD11b in LPS-stimulated microglia. Human microglia expressed PPAR-β and -γ, but not PPAR-α. Interestingly, either antisense knockdown of PPAR-β or antagonism of PPAR-β by a specific chemical antagonist abrogated gemfibrozil-mediated inhibition of microglial activation. On the other hand, blocking of PPAR-α and -γ had no effect on gemfibrozil-mediated anti-inflammatory effect in microglia. These results highlight the fact that gemfibrozil regulates microglial activation by inhibiting inflammatory gene expression in a PPAR-β dependent pathway and further reinforce its therapeutic application in several neuroinflammatory and neurodegenerative diseases.

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Acknowledgments

This study was supported by grants from National Institutes of Health (AT6681, NS64564 and NS71479) to Kalipada Pahan and National Multiple Sclerosis Society (RG4170-A-1) to Malabendu Jana.

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  1. Department of Neurological Sciences, Rush University Medical Center, 1735 West Harrison St., Suite 320, Chicago, IL, 60612, USA

    Malabendu Jana & Kalipada Pahan

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  1. Malabendu Jana
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Correspondence to Kalipada Pahan.

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Jana, M., Pahan, K. Gemfibrozil, a Lipid Lowering Drug, Inhibits the Activation of Primary Human Microglia Via Peroxisome Proliferator-Activated Receptor β. Neurochem Res 37, 1718–1729 (2012). https://doi.org/10.1007/s11064-012-0781-6

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  • DOI: https://doi.org/10.1007/s11064-012-0781-6

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