A new generation fatty acid amide hydrolase inhibitor protects against kainate-induced excitotoxicity.
Endocannabinoids, including anandamide (AEA), have been implicated in neuroprotective on-demand responses. Related to such a response to injury, an excitotoxic kainic acid (KA) injection (i.p.) was found to increase AEA levels in the brain. To modulate the endocannabinoid response during events of excitotoxicity in vitro and in vivo, we utilized a new generation compound (AM5206) that selectively inhibits the AEA deactivating enzyme fatty acid amide hydrolase (FAAH). KA caused calpain-mediated spectrin breakdown, declines in synaptic markers, and disruption of neuronal integrity in cultured hippocampal slices. FAAH inhibition with AM5206 protected against the neurodegenerative cascade assessed in the slice model 24 h postinsult. In vivo, KA administration induced seizures and the same neurodegenerative events exhibited in vitro. When AM5206 was injected immediately after KA in rats, the seizure scores were markedly reduced as were levels of cytoskeletal damage and synaptic protein decline. The pre- and postsynaptic proteins were protected by the FAAH inhibitor to levels comparable to those found in healthy control brains. These data support the idea that endocannabinoids are released and converge on pro-survival pathways that prevent excitotoxic progression.
Biotechnology Research and Training Center, University of North Carolina Pembroke, 115 Livermore Drive, Pembroke, NC 28372-1510, USA.
Vinogran
V
Naidoo
Spyros P
SP
Nikas
David A
DA
Karanian
Jeannie
J
Hwang
Jianhong
J
Zhao
JodiAnne T
JT
Wood
Shakiru O
SO
Alapafuja
Subramanian K
SK
Vadivel
David
D
Butler
Alexandros
A
Makriyannis
Ben A
BA
Bahr
D000581:Amidohydrolases / Q000037:antagonists & inhibitors*; D000818:Animals; D001095:Arachidonic Acids / Q000378:metabolism; D063385:Cannabinoid Receptor Modulators / Q000494:pharmacology*; D063388:Endocannabinoids; D006624:Hippocampus / Q000187:drug effects* / Q000378:metabolism; D007608:Kainic Acid / Q000633:toxicity*; D010647:Phenyl Ethers / Q000494:pharmacology*; D053284:Polyunsaturated Alkamides / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D012640:Seizures / Q000139:chemically induced; D046509:Tissue Culture Techniques; D000099252:Fatty Acid Amide Hydrolases
D000581:Amidohydrolases; D001095:Arachidonic Acids; D063385:Cannabinoid Receptor Modulators; D063388:Endocannabinoids; D007608:Kainic Acid; D010647:Phenyl Ethers; D053284:Polyunsaturated Alkamides; D000099252:Fatty Acid Amide Hydrolases; C559613:AM 5206; C078814:anandamide