Enhancement of endocannabinoid signaling by fatty acid amide hydrolase inhibition: a neuroprotective therapeutic modality.
OBJECTIVE
This review posits that fatty acid amide hydrolase (FAAH) inhibition has therapeutic potential against neuropathological states including traumatic brain injury; Alzheimer's, Huntington's, and Parkinson's diseases; and stroke.


METHODS
This proposition is supported by data from numerous in vitro and in vivo experiments establishing metabolic and pharmacological contexts for the neuroprotective role of the endogenous cannabinoid ("endocannabinoid") system and selective FAAH inhibitors.


RESULTS
The systems biology of endocannabinoid signaling involves two main cannabinoid receptors, the principal endocannabinoid lipid mediators N-arachidonoylethanolamine ("anandamide") (AEA) and 2-arachidonoyl glycerol (2-AG), related metabolites, and the proteins involved in endocannabinoid biosynthesis, biotransformation, and transit. The endocannabinoid system is capable of activating distinct signaling pathways on-demand in response to pathogenic events or stimuli, thereby enhancing cell survival and promoting tissue repair. Accumulating data suggest that endocannabinoid system modulation at discrete targets is a promising pharmacotherapeutic strategy for treating various medical conditions. In particular, neuronal injury activates cannabinoid signaling in the central nervous system as an intrinsic neuroprotective response. Indirect potentiation of this salutary response through pharmacological inhibition of FAAH, an endocannabinoid-deactivating enzyme, and consequent activation of signaling pathways downstream from cannabinoid receptors have been shown to promote neuronal maintenance and function.


CONCLUSIONS
This therapeutic modality has the potential to offer site- and event-specific neuroprotection under conditions where endocannabinoids are being produced as part of a physiological protective mechanism. In contrast, direct application of cannabinoid receptor agonists to the central nervous system may activate CB receptors indiscriminately and invite unwanted psychotrophic effects.
Hwang
Jeannie
J
Department of Pharmaceutical Sciences and the Neurosciences Program, University of Connecticut, Storrs, Connecticut, USA.
Adamson
Crista
C
Butler
David
D
Janero
David R
DR
Makriyannis
Alexandros
A
Bahr
Ben A
BA
D000581:Amidohydrolases / Q000037:antagonists & inhibitors*; D000818:Animals; D063385:Cannabinoid Receptor Modulators / Q000378:metabolism*; D016503:Drug Delivery Systems; D063388:Endocannabinoids; D006801:Humans; D009422:Nervous System Diseases / Q000188:drug therapy* / Q000503:physiopathology; D019636:Neurodegenerative Diseases / Q000188:drug therapy / Q000503:physiopathology; D018696:Neuroprotective Agents / Q000494:pharmacology / Q000627:therapeutic use; D015398:Signal Transduction / Q000187:drug effects; D000099252:Fatty Acid Amide Hydrolases
D000581:Amidohydrolases; D063385:Cannabinoid Receptor Modulators; D063388:Endocannabinoids; D018696:Neuroprotective Agents; D000099252:Fatty Acid Amide Hydrolases