Activity of FAAH-Inhibitor JZP327A in an Experimental Rat Model of Migraine

Abstract

Increased anandamide levels via fatty acid amide hydrolase (FAAH) inhibition can decrease the pronociceptive responses and inflammatory mediators in animal models of migraine. Here, we profile the pharmacological activity of the FAAH inhibitor JZP327A, a chiral 1,3,4-oxadiazol-2(3H)-one compound, in the mediation of spontaneous and nocifensive behaviour in the animal models of migraine based on nitroglycerin (NTG) administration. JZP327A (0.5 mg/kg, i.p.) or vehicle was administered to male rats 3 h after NTG (10 mg/kg, i.p.) or NTG vehicle injection. The rats were then exposed to the open field test and an orofacial formalin test 1 h later. The levels of endocannabinoids and lipid-related substances, and the expression of pain and inflammatory mediators were evaluated in cranial tissues and serum. The findings show that JZP327A did not affect NTG-induced changes in the spontaneous behaviour of rats, while it inhibited NTG-induced hyperalgesia at the orofacial formalin test. Furthermore, JZP327A dramatically decreased the gene expression of calcitonin gene-related peptide (CGRP), tumor necrosis factor alpha (TNF-alpha) and interleukin 6 (IL-6) in the trigeminal ganglia and medulla-pons, while it did not change endocannabinoids or lipids levels nor CGRP serum levels in the same tissues. These data suggest an anti-hyperalgesic role for JZP327A in the NTG model, which is mediated by the inhibition of the inflammatory cascade of events. This activity does not seem mediated by a change in the levels of endocannabinoids and lipid amides.

URB937 Prevents the Development of Mechanical Allodynia in Male Rats with Trigeminal Neuralgia

“…Nonetheless, in both experimental paradigms, the FAAH inhibitor proved to be able to reduce the IoN-CCI-induced upregulation of the pain neuropeptide CGRP and proinflammatory cytokines TNF-alpha and IL-1beta and to increase the anti-inflammatory cytokine IL-10 in trigeminal-related areas. The present findings are consistent with previous studies in which FAAH inhibitors were able to alter the gene expression of pain and inflammatory mediators [33][34][35][36][37][38]. However, based on the discrepancies observed in these two different experimental settings, it appears that changes in gene expression of the mediators evaluated in this study are not directly associated with mechanical pain, thus suggesting that other signalling pathways and mediators are involved.…”

Endocannabinoid Hydrolase Inhibitors: Potential Novel Anxiolytic Drugs

“… 181 JZP327A (IC 50 = 11 nM), synthesized using 1,3,4-oxadiazol-2-ones as a scaffold, is a highly selective, slowly reversible FAAH inhibitor 182 with good analgesic effects. 183 FAAH inhibitors developed on the basis of carbamates also exhibit good selectivity, reversibility, water solubility and some neuroprotective effects. 184 …”

“…181 JZP327A (IC 50 = 11 nM), synthesized using 1,3,4-oxadiazol-2-ones as a scaffold, is a highly selective, slowly reversible FAAH inhibitor 182 with good analgesic effects. 183 FAAH inhibitors developed on the basis of carbamates also exhibit good selectivity, reversibility, water solubility and some neuroprotective effects. 184 Three-dimensional quantitative structure-activity relationship (3D-QSAR) model, which can better represent the structure-activity relationship of ligand-enzyme interaction and help to develop more effective compounds, has been widely used in FAAH inhibitor development.…”

Navigating the Neurobiology of Migraine: From Pathways to Potential Therapies

“…The authors of recent studies have identified several potential targets, including enzymes, ion channels, and signaling pathways, each of which contribute uniquely to our understanding of migraine and offer new opportunities for therapeutic intervention [88,[99][100][101][102]. Three papers delve into the specifics of these experimental models and therapeutic targets, providing a thorough overview of current progress and future directions in migraine research [69][70][71].…”

“…Greco et al investigated the potential therapeutic benefits of targeting the endocannabinoid system in the context of migraine pathophysiology [69]. Utilizing a male rat model, the authors examined the effects of trigeminal hyperalgesia using AKU-005, a dual fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL) inhibitor.…”