Journal
NEUROCHEMICAL RESEARCH
Volume 37, Issue 8, Pages 1718-1729Publisher
SPRINGER/PLENUM PUBLISHERS
DOI: 10.1007/s11064-012-0781-6
Keywords
Gemfibrozil; Human microglia; Proinflammatory molecules; CD11b; PPAR-alpha/beta/gamma
Categories
Funding
- National Institutes of Health [AT6681, NS64564, NS71479]
- National Multiple Sclerosis Society [RG4170-A-1]
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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 PPAR beta/delta 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-beta and -gamma, but not PPAR-alpha. Interestingly, either antisense knockdown of PPAR-beta or antagonism of PPAR-beta by a specific chemical antagonist abrogated gemfibrozil-mediated inhibition of microglial activation. On the other hand, blocking of PPAR-alpha and -gamma 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-beta dependent pathway and further reinforce its therapeutic application in several neuroinflammatory and neurodegenerative diseases.
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