The ECS as Therapeutic Target

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As far as potential clinical applications are concerned, CB1 antagonists cross the blood brain barrier and rimonabant, the best known CB1 antagonist, was first approved for the treatment of obesity in Europe, but then withdrawn from the market because of serious central side effects, such as depression and anxiety. However, a new class of peripheral restricted CB1 antagonists has been recently developed that do not cross the blood-brain barrier and are thus devoid of psychoactive effects, while retaining their peripheral beneficial effects [132]. There is thus increasing interest on the potential use of these compounds for the treatment of diabetes and diabetes-related complications, including DN.

Selective CB2 agonists are free from central side effects and promising tools for treatment of chronic diseases associated with a low grade inflammation. A number of pharmaceutical companies have reported entering development with CB2 agonists, such as KHK6188b, ABT-521b, APD371, and S-777469, mostly for the treatment of pain. Insofar there are no ongoing trials testing the efficacy of these compounds in DN; however, this area of research is appealing as CB2 activation has also beneficial effects in animal models of atherosclerosis [133], cardiac injury [134], and diabetic neuropathy [135], raising the possibility that CB2 agonism may have positive effects on multiple vascular bed of diabetic complications. However, in many injury models, CB2 agonists appear to be most effective when given before the initiation of the insult, and may lose their efficacy or even promote inflammation when given at later time [136]. Furthermore, there is experimental evidence that CB2 activation may worsen obesity-driven inflammation in target organ of metabolism [137]. Thus, a better understanding of the underlying mechanisms is required for the development of meaningful therapeutic approaches. Finally, given the close relationship between the two EC receptors that share ligands and have also intertwined intracellular signalling pathways, a combined approach with CB1 antagonists and CB2 agonists may results in further benefit.