The Pharmacological Inhibition of Fatty Acid Amide Hydrolase Prevents Excitotoxic Damage in the Rat Striatum: Possible Involvement of CB1 Receptors Regulation

Abstract

The endocannabinoid system (ECS) actively participates in several physiological processes within the central nervous system. Among such, its involvement in the downregulation of the N-methyl-D-aspartate receptor (NMDAr) through a modulatory input at the cannabinoid receptors (CBr) has been established. After its production via the kynurenine pathway (KP), quinolinic acid (QUIN) can act as an excitotoxin through the selective overactivation of NMDAr, thus participating in the onset and development of neurological disorders. In this work, we evaluated whether the pharmacological inhibition of fatty acid amide hydrolase (FAAH) by URB597, and the consequent increase in the endogenous levels of anandamide, can prevent the excitotoxic damage induced by QUIN. URB597 (0.3 mg/kg/day × 7 days, administered before, during and after the striatal lesion) exerted protective effects on the QUIN-induced motor (asymmetric behavior) and biochemical (lipid peroxidation and protein carbonylation) alterations in rats. URB597 also preserved the structural integrity of the striatum and prevented the neuronal loss (assessed as microtubule-associated protein-2 and glutamate decarboxylase localization) induced by QUIN (1 μL intrastriatal, 240 nmol/μL), while modified the early localization patterns of CBr1 (CB1) and NMDAr subunit 1 (NR1). Altogether, these findings support the concept that the pharmacological manipulation of the endocannabinoid system plays a neuroprotective role against excitotoxic insults in the central nervous system.

Cannabinoid-profiled agents improve cell survival via reduction of oxidative stress and inflammation, and Nrf2 activation in a toxic model combining hyperglycemia+Aβ1-42 peptide in rat hippocampal neurons

“…FAAH is widely localized throughout the brain, and FAAH-positive neurons have been found in the proximity of nerve terminals containing CB1 in the neocortex, hippocampus and basal ganglia (De Petrocellis et al, 2004). The pharmacological tool [3-(3carbamoylphenyl)phenyl]N-cyclohexylcarbamate (URB597) exhibits unique therapeutic potential as it is capable of inhibiting FAAH activity, thereby leading to accumulation of endocannabinoids, such as AEA and oleamide (Aguilera-Portillo et al, 2019;Maya-López et al, 2019). 2-Arachidonoylglycerol (2-AG), another major endocannabinoid which is mainly degraded by monoacylglycerol lipase (MAGL), has been shown to activate CB1 and CB2 receptors, in turn, exerting neuroprotective effects (Dinh et al, 2002;Mounsey et al, 2015).…”

Potential and Limits of Cannabinoids in Alzheimer’s Disease Therapy

“…Currently, several classes of reversible and irreversible covalent FAAH inhibitors have been developed, such as URB597, OL-135, PF-3845, AM3506, PF-04457845, JNJ-40355003, JNJ-42165279, JNJ-1661010, and BIA 10-2474, although the majority of studies have involved URB597. The irreversible covalent URB597 promoted the increase in endocannabinoid anandamide by inhibiting FAAH activity [ 145 , 146 ]. Furthermore, URB597 efficiently suppressed glutamate Aβ42-induced toxicity in primary hippocampal neurons and stimulated the mitochondrial membrane potential [ 147 ].…”

A Guide to Targeting the Endocannabinoid System in Drug Design

“…It has been shown that deletion of CB1 accelerates brain aging through tumor necrosis factor α (TNF-α) [166], while CB1 agonism decreases neuroinflammation [167]. There have also been studies on FAAH inhibition impact on decreasing neuroinflammation [168] and exitoxicity in rodent models [169]. Moreover, a GPR55 inverse agonist, KIT 17, in vitro inhibited PGE2 release in microglia (cells important for CNS immune functions), and thus may be further studied as a potential anti-neuroinflammatory agent [170].…”