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Cannabinoid activation of PPARα; a novel neuroprotective mechanism

By Y. Sun, S.P.H. Alexander, M.J. Garle, Claire L. Gibson, K. Hewitt, Sean P. Murphy, D.A. Kendall and A.J. Bennett

Abstract

Full text of this item is not currently available on the LRA. \ud The final published version is available at http://www3.interscience.wiley.com/journal/121667860/issue, Doi: 10.1038/sj.bjp.0707478.Background and purpose: Although CB1 receptor activation evokes neuroprotection in response to cannabinoids, some cannabinoids have been reported to be peroxisome proliferator activated receptor (PPAR) ligands, offering an alternative protective mechanism. We have, therefore, investigated the ability of a range of cannabinoids to activate PPARα and for N-oleoylethanolamine (OEA), an endogenous cannabinoid-like compound (ECL), to evoke neuroprotection.\ud Experimental approach: Assays of PPARα occupancy and gene transactivation potential were conducted in cell-free and transfected HeLa cell preparations, respectively. In vivo estimates of PPARα activation through fat mobilization and gene transcription were conducted in mice. Neuroprotection in vivo was investigated in wild-type and PPARα gene-disrupted mice.\ud Key results: The ECLs OEA, anandamide, noladin ether and virodhamine were found to bind to the purified PPARα ligand binding domain and to increase PPARα-driven transcriptional activity. The high affinity synthetic CB1/2 cannabinoid agonist WIN 55212-2 bound to PPARα equipotently with the PPARα agonist fenofibrate, and stimulated PPARα-mediated gene transcription. The phytocannabinoid ∆9 tetrahydrocannabinol was without effect. OEA and WIN 55212-2 induced lipolysis in vivo, while OEA pre-treatment reduced infarct volume from middle cerebral artery occlusion in wild-type, but not in PPARα-null mice. OEA treatment also led to increased expression of the NFkB-inhibitory protein, IkB, in mouse cerebral cortex, while expression of the NFkB-regulated protein COX-2 was inhibited.\ud Conclusions and implications: These data demonstrate the potential for a range of cannabinoid compounds, of diverse structures, to activate PPARα and suggest that at least some of the neuroprotective properties of these agents could be mediated by nuclear receptor activation

Topics: cannabinoids, N-oleoylethanolamine, peroxisome proliferator-activated receptors (PPARs), neuroprotection
Publisher: Nature Publishing Group
Year: 2007
DOI identifier: 10.1038/sj.bjp.0707478
OAI identifier: oai:lra.le.ac.uk:2381/8005
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