Development of cannabinoid-based therapies for Parkinson’s disease: emphasis on targeting cannabinoid receptors as CB2, PPAR-γ and GPR55 receptors

Cannabinoids are a singular family of plant-derived compounds, endogenous signaling lipids and synthetic derivatives able to show therapeutic properties, among others, to afford neuroprotection in neurodegenerative pathologies. One of these pathologies is Parkinson’s disease (PD), for which certain cannabinoids have been found to alleviate specific motor and non-motor signs. However, their most relevant therapeutic contribution in PD may come from their neuroprotective properties, which, in this disease, are facilitated by the abundant presence in the basal ganglia of specific receptors (e.g., CB1, CB2, GPR55, PPAR-γ) available for the endocannabinoid action. These receptors are located in glutamatergic and GABAergic neurons, astrocytes, microglial cells, and other cell substrates in the basal ganglia, where they may play a critical role in the preservation, rescue, repair and/or replacement of neurons against the numerous insults that contribute to PD pathogenesis. This review will collect all the preclinical evidence supporting the action of cannabinoids as neuroprotective agents in PD. This work was initiated more than 20 years ago with the phytocannabinoid cannabidiol, but more recently concentrated on specific cannabinoids such as Δ9-tetrahydrocannabidivarin, the cannabigerol derivative VCE-003.2, and the pyrazole derivative VCE-006.1. These compounds have recruited the maximal interest in the last years because their activity at CB2, PPAR-γ and GPR55, respectively. The preclinical studies carried out with these compounds have demonstrated efficacy in experimental models then supporting the interest to progress in the next years towards their prompt clinical validation as neuroprotective agents for PD, which lacks effective treatments for delaying disease progression.