Endocannabinoid enhancement protects against kainic acid-induced seizures and associated brain damage.
Endocannabinoids are released in response to pathogenic insults, and inhibitors of endocannabinoid inactivation enhance such on-demand responses that promote cellular protection. Here, AM374 (palmitylsulfonyl fluoride), an irreversible inhibitor of fatty acid amide hydrolase (FAAH), was injected i.p. into rats to test for endocannabinoid enhancement. AM374 caused a prolonged elevation of anandamide levels in several brain regions, including the hippocampus, and resulted in rapid activation of the extracellular signal regulated-kinase/mitogen-activated protein kinase pathway that has been linked to survival. To evaluate the neuroprotective nature of the FAAH inhibitor, we tested AM374 in a seizure model involving rats insulted with kainic acid (KA). AM374 was injected immediately after KA administration, and seizure scores were significantly reduced throughout a 4-h observation period. The KA-induced seizures were associated with calpain-mediated cytoskeletal breakdown, reductions in synaptic markers, and loss of CA1 hippocampal neurons. FAAH inhibition protected against the excitotoxic damage and neuronal loss assessed 48 h postinsult. AM374 also preserved pre- and postsynaptic markers to levels comparable with those found in noninsulted animals, and the synaptic marker preservation strongly correlated with reduced seizure scores. With regard to behavioral deficits in the excitotoxic rats, AM374 produced nearly complete functional protection, significantly improving balance and coordination across different behavioral paradigms. These data indicate that AM374 crosses the blood-brain barrier, enhances endocannabinoid responses in key neuronal circuitries, and protects the brain against excitotoxic damage.
Karanian
David A
DA
Department of Pharmaceutical Sciences, University of Connecticut, Storrs, CT 06269-3092, USA. david.karanian@uconn.edu
Karim
Sanjida L
SL
Wood
JodiAnne T
JT
Williams
John S
JS
Lin
Sonyuan
S
Makriyannis
Alexandros
A
Bahr
Ben A
BA
D000581:Amidohydrolases / Q000037:antagonists & inhibitors; D000818:Animals; D001095:Arachidonic Acids / Q000032:analysis; D001921:Brain / Q000378:metabolism / Q000473:pathology; D063385:Cannabinoid Receptor Modulators / Q000502:physiology*; D063388:Endocannabinoids; D006624:Hippocampus / Q000473:pathology; D007608:Kainic Acid / Q000009:adverse effects*; D020935:MAP Kinase Signaling System; D018696:Neuroprotective Agents / Q000493:pharmacokinetics / Q000494:pharmacology; D010168:Palmitates / Q000493:pharmacokinetics / Q000494:pharmacology; D053284:Polyunsaturated Alkamides / Q000032:analysis; D051381:Rats; D012640:Seizures / Q000139:chemically induced*; D000099252:Fatty Acid Amide Hydrolases
D000581:Amidohydrolases; D001095:Arachidonic Acids; D063385:Cannabinoid Receptor Modulators; D063388:Endocannabinoids; D007608:Kainic Acid; D018696:Neuroprotective Agents; D010168:Palmitates; D053284:Polyunsaturated Alkamides; D000099252:Fatty Acid Amide Hydrolases; C104963:AM 374; C078814:anandamide