Cannabinoid receptor type 2 as a therapeutic target for Parkinson's disease

Abstract Cannabinoid receptor types 1 and 2 (CB1R and CB2R), the endogenous ligands, and their specific synthesizing and degrading enzymes constitute the endocannabinoid system. The different elements of this system are very abundant in the brain, where they modulate multiple functions such as synaptic transmission, immunological responses, and cell proliferation. In the nervous system, CB2Rs are preferentially expressed in activated microglial cells and in some restricted neuronal populations. The pharmacology of CB2Rs is complex; agonists induce distinct activation profiles that might lead to different therapeutic effects. Furthermore, CB2Rs can heteromerize with other receptors to generate new and unique signaling units that provide novel pharmacological targets. Two strategies have been used to evaluate the therapeutic potential of CB2R in Parkinson's disease (PD). Direct activation of CB2Rs with agonists protects dopaminergic neurons from degeneration in animal models of the disease by decreasing neuroinflammation. Inhibition of endocannabinoid degradation increases the levels of endogenous ligands in the brain. Both endocannabinoids, 2-arachidonoyl glycerol and anandamide, have antiparkinsonian properties; 2-AG is neuroprotective, and anandamide provides symptomatic relief. Clinical trials with different types of compounds and cannabis extracts do not show consistent results but point toward a beneficial effect in different PD symptoms and dyskinesias. Preclinical and clinical studies suggest that the endocannabinoid system could be an interesting therapeutic target for PD, specifically with respect to CB2Rs.