Cannabinoid activation of PPAR alpha; a novel neuroprotective mechanism.
OBJECTIVE
Although CB(1) 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 PPAR alpha and for N-oleoylethanolamine (OEA), an endogenous cannabinoid-like compound (ECL), to evoke neuroprotection.


METHODS
Assays of PPAR alpha occupancy and gene transactivation potential were conducted in cell-free and transfected HeLa cell preparations, respectively. In vivo estimates of PPAR alpha activation through fat mobilization and gene transcription were conducted in mice. Neuroprotection in vivo was investigated in wild-type and PPAR alpha gene-disrupted mice.


RESULTS
The ECLs OEA, anandamide, noladin ether and virodhamine were found to bind to the purified PPAR alpha ligand binding domain and to increase PPAR alpha-driven transcriptional activity. The high affinity synthetic CB(1/2) cannabinoid agonist WIN 55212-2 bound to PPAR alpha equipotently with the PPARalpha agonist fenofibrate, and stimulated PPARalpha-mediated gene transcription. The phytocannabinoid delta 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 PPAR alpha-null mice. OEA treatment also led to increased expression of the NFkappa B-inhibitory protein, Ikappa B, in mouse cerebral cortex, while expression of the NFkappa B-regulated protein COX-2 was inhibited.


CONCLUSIONS
These data demonstrate the potential for a range of cannabinoid compounds, of diverse structures, to activate PPAR alpha and suggest that at least some of the neuroprotective properties of these agents could be mediated by nuclear receptor activation.
Sun
Y
Y
School of Biomedical Sciences, University of Nottingham Medical School, Nottingham, UK.
Alexander
S P H
SP
Garle
M J
MJ
Gibson
C L
CL
Hewitt
K
K
Murphy
S P
SP
Kendall
D A
DA
Bennett
A J
AJ
D000818:Animals; D001095:Arachidonic Acids / Q000378:metabolism / Q000494:pharmacology; D048588:Benzoxazines / Q000378:metabolism / Q000494:pharmacology; D002186:Cannabinoids / Q000378:metabolism* / Q000494:pharmacology; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism; D051546:Cyclooxygenase 2 / Q000378:metabolism; D013759:Dronabinol / Q000378:metabolism / Q000494:pharmacology; D063388:Endocannabinoids; D005231:Fatty Acids, Unsaturated / Q000494:pharmacology; D011345:Fenofibrate / Q000378:metabolism / Q000494:pharmacology; D006367:HeLa Cells; D006801:Humans; D051550:I-kappa B Kinase / Q000378:metabolism; D008024:Ligands; D008156:Luciferases / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009025:Morpholines / Q000378:metabolism / Q000494:pharmacology; D009281:Naphthalenes / Q000378:metabolism / Q000494:pharmacology; D018696:Neuroprotective Agents / Q000378:metabolism* / Q000494:pharmacology; D009829:Oleic Acids / Q000378:metabolism / Q000494:pharmacology; D047493:PPAR alpha / Q000819:agonists / Q000235:genetics / Q000378:metabolism*; D053284:Polyunsaturated Alkamides / Q000378:metabolism / Q000494:pharmacology; D011485:Protein Binding; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D014162:Transfection
D001095:Arachidonic Acids; D048588:Benzoxazines; D002186:Cannabinoids; D063388:Endocannabinoids; D005231:Fatty Acids, Unsaturated; D008024:Ligands; D009025:Morpholines; D009281:Naphthalenes; D018696:Neuroprotective Agents; D009829:Oleic Acids; C440229:Oleylethanolamide; D047493:PPAR alpha; D053284:Polyunsaturated Alkamides; D011993:Recombinant Fusion Proteins; C456739:virodhamine; C070417:(3R)-((2,3-dihydro-5-methyl-3-((4-morpholinyl)methyl)pyrrolo-(1,2,3-de)-1,4-benzoxazin-6-yl)(1-naphthalenyl))methanone; D013759:Dronabinol; D008156:Luciferases; D051546:Cyclooxygenase 2; D051550:I-kappa B Kinase; C013641:parinaric acid; D011345:Fenofibrate; C078814:anandamide