Enhancement of endocannabinoid signaling by fatty acid amide hydrolase inhibition: A neuroprotective therapeutic modality

Abstract

Aim-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.Main 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 ("endocannbinoid") system and selective FAAH inhibitors.Key Findings-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.Significance-This therapeutic modality has the potential to offer site-and event-specific therapeutic relief in those tissues 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.

Equipotent Inhibition of Fatty Acid Amide Hydrolase and Monoacylglycerol Lipase – Dual Targets of the Endocannabinoid System to Protect against Seizure Pathology

“…According to Long et al [66], dual augmentation of the AEA and 2-AG signaling pathways allows these 2 lipid transmitters to engage in extensive crosstalk. A critical balance between AEA and 2-AG levels, controlled by endocannabinoid synthesizing and metabolizing enzymes, may therefore be important for normal physiological processes, as well as to promote repair after pathological events [1,45,48,67]. Dual FAAH/MAGL inhibitors may thus be more viable as neuroprotectants against excitotoxic brain injury.…”

“…Neuronal degeneration and death arising from excessive excitatory activity reflect the vulnerability of the brain to excitotoxic insults. In the excitotoxicity field, much attention has been applied to potential strategies to preserve learning and memory and other brain functions, including the neuroprotective abilities of specific signaling lipids that make up the family of endocannabinoids (for more detail see Hwang J, et al [1] Zanettini C, et al [2], Pacher and Hasko [3], and Janero DR, et al [4]). Multiple studies have linked the principal endocannabinoids in the central nervous system, anandamide (AEA) and 2-arachidonoyl glycerol (2-AG), with protection against numerous diseases, including Alzheimer's, Parkinson's, and Huntington's disease, epileptic seizures, and stroke/ischemic brain damage [5][6][7][8][9][10][11][12][13][14].…”

“…Studies have shown that systemically administered kainic acid (KA) treatment elevates AEA levels in the brain [14,[31][32][33]. Related to this response to injury, FAAH inhibition enhanced the salutary effects of cannabinergic signaling in the rat hippocampus, mediated predominantly via CB1 receptors [1,14,34,35]. It has been suggested that CB1 receptor activation reduces excessive glutamatergic signaling and excitotoxic progression thereby protecting hippocampal cells from cytoskeletal and synaptic damage [13,14,32,33,36].…”

Dietary docosahexaenoic acid supplementation alters select physiological endocannabinoid-system metabolites in brain and plasma

“…Multiple reaction monitoring of the endocannabinoid metabolome and the corresponding deuterated internal standards was Defi ning the extent to which specifi c dietary components can modulate the physiological endocannabinoid metabolome has been highlighted as an important contemporary research goal ( 10,(12)(13)(14)(15) ( 14,(16)(17)(18), from which AEA and AG are derived ( 1,3 ). AA and DHA are supplied to the brain from the circulation, either from dietary sources or as synthesized primarily in the liver from shorter-chain essential fatty acids ( 19,20 ).…”

“…Endocannabinoid signaling is ubiquitous in mammals, being particularly critical in brain , where it modulates neurotransmitter release and exhibits neuroprotective effects ( 2, 3 ). Although the fi rst two endocannabinoids identifi ed, N -arachidonoylethanolamine (anandamide, AEA) and 2-arachidonoylglycerol (AG), have been extensively characterized, the (patho)physiological impact of endocannabinoid signaling has prompted the search for additional endocannabinoids and their related metabolites/ biosynthetic precursors, creating an evolving network of chemical species collectively termed the endocannabinoid metabolome, few of which have been functionally annotated ( 1,(3)(4)(5)(6)(7)(8)(9). Although the translational and diagnostic aspects of endocannabinoid signaling are well appreciated ( 10, 11 ), factors that infl uence and regulate the endocannabinoid metabolome profi le among various tissues and compartments remains incompletely described and understood ( 1, 10 ), as are the metabolome's relationship to lipid pathways outside of the endocannabinoid signaling system ( 3, 9 ).…”