title: The fatty acid amide hydrolase inhibitor, URB597, promotes retinal ganglion cell neuroprotection in a rat model of optic nerve axotomy.
abstract: The endocannabinoid, N-arachidonoylethanolamine (AEA), is degraded by the enzyme fatty acid amide hydrolase (FAAH). This study examined whether the FAAH inhibitor, URB597, increases retinal ganglion cell (RGC) survival following optic nerve axotomy in young and aged animals. URB597 alone, or together with either a CB1 or CB2 receptor antagonist, was administered daily for 1 or 2 weeks post-axotomy. Histological assessment of retinas indicated that URB597 increased RGC survival in young retina at 1 and 2 weeks post-axotomy. The increase in RGC survival at 2 weeks was accompanied by a reduction in phagocytic microglia. The CB1 antagonist, AM281, but not the CB2 antagonist, AM630, ablated URB597-mediated RGC neuroprotection. CB1 or CB2 antagonism increased phagocytic microglia in URB597 and vehicle-treated animals. In aged animals, URB597 increased RGC survival at 1 week, but not at 2 weeks post-axotomy and had no effect on microglia. Retinal Iba-1 positive microglia were also decreased in URB597-treated axotomized young animals and this decrease was mitigated by CB1 but not CB2 antagonism. As seen with phagocytotic microglia, the CB2 antagonist, AM630, increased Iba-1 positive microglia in the absence of URB597 treatment. Measurement of retinal endocannabinoid levels in URB597-treated animals at 2 weeks post-axotomy revealed a significant increase in AEA levels, accompanied by a decrease in the AEA metabolite, N-arachidonoyl glycine, in young animals but not aged animals. 2-arachidonoylglycerol levels were similar across all experimental groups. These data demonstrate that URB597-mediated retinal neuroprotective effects are mediated primarily through CB1 receptors and that URB597 neuroprotective efficacy declines with age.
authors: Department of Pharmacology, Faculty of Medicine, Dalhousie University, Halifax, Nova Scotia, Canada.
authors: Joanna E
authors: JE
authors: Slusar
authors: Elizabeth A
authors: EA
authors: Cairns
authors: Anna-Maria
authors: AM
authors: Szczesniak
authors: Heather B
authors: HB
authors: Bradshaw
authors: Adriana
authors: A
authors: Di Polo
authors: Melanie E M
authors: ME
authors: Kelly
mesh_terms: D000367:Age Factors; D000581:Amidohydrolases / Q000378:metabolism; D000818:Animals; D019771:Axotomy; D001549:Benzamides / Q000494:pharmacology* / Q000627:therapeutic use; D002219:Carbamates / Q000494:pharmacology* / Q000627:therapeutic use; D002452:Cell Count; D004195:Disease Models, Animal; D063388:Endocannabinoids / Q000378:metabolism; D007211:Indoles / Q000494:pharmacology; D017628:Microglia / Q000187:drug effects; D009025:Morpholines / Q000494:pharmacology; D009434:Neural Pathways / Q000378:metabolism / Q000473:pathology; D018696:Neuroprotective Agents / Q000494:pharmacology* / Q000627:therapeutic use; D009901:Optic Nerve Diseases / Q000188:drug therapy / Q000473:pathology*; D011720:Pyrazoles / Q000494:pharmacology; D051381:Rats; D011916:Rats, Inbred F344; D012160:Retina / Q000378:metabolism / Q000473:pathology*; D012165:Retinal Ganglion Cells / Q000187:drug effects*; D013266:Stilbamidines; D000099252:Fatty Acid Amide Hydrolases
chemical_list: D000581:Amidohydrolases; D001549:Benzamides; D002219:Carbamates; D063388:Endocannabinoids; D007211:Indoles; D009025:Morpholines; D018696:Neuroprotective Agents; D011720:Pyrazoles; D013266:Stilbamidines; D000099252:Fatty Acid Amide Hydrolases; C049774:2-hydroxy-4,4'-diamidinostilbene, methanesulfonate salt; C500528:cyclohexyl carbamic acid 3'-carbamoylbiphenyl-3-yl ester; C109925:AM 281; C094023:iodopravadoline