The endogenous cannabinoid system (ECS) has been described as a conserved lipid-signalling network modulating neuronal functions and inflammatory processes, potentially involved in the aetiology of certain human lifestyle diseases. Endogenous cannabinoids (ECBs), such as Anandamide (AEA) and 2-arachidonoylglycerol (2-AG), activate type-1 and type-2 cannabinoid receptors (CB1R and CB2R) to modulate a wide range of responses (pain, appetite, motility, sleep, thermoregulation, cognitive and emotional states) and the actions of these signalling lipids are rapidly terminated by cellular reuptake and subsequent hydrolysis operated by a number of enzymes. The fatty acid amide hydrolase (FAAH) was originally identified as the enzyme responsible for AEA hydrolysis and to be also the main regulator of the endogenous tone of AEA in vivo. In addition to FAAH, monoacylglycerol lipase (MGL) was later identified as additional ECBs-metabolizing enzyme, playing a pivotal role in the catabolism and homeostasis of the 2-AG in the central nervous system.(1)
Figure 1. – Schematic representation of the main elements of the ECS.
In the past few years, an increasing body of evidence has suggested the ECS as a valuable target in several neurological and neurodegenerative diseases, since a hypofunctionality or dysregulation of this system may be responsible for some of the symptomatology of Alzheimer Disease, Huntington Disease, Multiple Sclerosis (MS), and Amyotrophic lateral sclerosis.(2)
Giving that, small molecules able to modulate the ECS, by inhibiting ECBs degrading enzymes and increasing ECBs tissue levels, could represent an interesting tool to address the abovementioned pathologies. These compounds are also less likely to cause psychoactive effects related to direct agonism of CB1R while maintaining the beneficial effects of CB1R/CB2R activation.(3)
Some interesting results have been achieved with the synthesis of a novel class of potent and selective MGL inhibitors tested in mice suffering from experimental autoimmune encephalomyelitis (EAE), a rodent demyelinating disease model universally accepted as an animal model of MS.(4) As proposed, in vivo administration of MGL inhibitors reduces the clinical severity of the EAE, induces re-myelinisation of damaged neurons and diminishes neuroinflammation. These encouraging results support the hypothesis of a tight intersection between the ECS and MS, suggesting MGL inhibition as an innovative therapeutic approach for treating MS.
Other recent investigations have addressed the involvement of ECS and ECBs levels in autism.(5) Being this uniquely human, there are only a few validated animal models useful to clarify the effects of ECBs-metabolizing enzymes inhibitors. However, an inherited disorder called Fragile X syndrome (FXS), caused by mutations in the fmr1 protein, produces autistic features in a high percentage of patients affected by this pathology. Thus, fmr1 knockout mice provide a good animal model to identify novel targets for autism. It has been reported that the ablation of fmr1 gene also causes dysfunctions on 2-AG metabolism. Then, stimulation of 2-AG signalling could be a useful treatment for mitigating FXS symptoms, since it is able to restore synaptic activity through type I metabotropic glutamate activation. These evidences highlight once again how important is the role of ECS in neurological disorders, pointing out the usefulness of efficient ECS tone modulators.
Blog by Samuele Maramai
- Pharmacol Rev. 2006, 58 (3), 389–462
- British Journal of Pharmacology, 2010, 160, 480–498
- Recent Patents on CNS Drug Discovery, 2012, 7, 49-70
- J. Med. Chem. 2016, 59, 2612−2632
- Neurotherapeutics, 2015, 12, 837–847