Cannabinoid CB2 Receptors as a New Target for the Treatment of Disease Progression in Parkinson's Disease: Studies in LRRK2-Transgenic Pre-clinical Models

Objective/Rationale:             
Cannabinoids provide neuroprotection in neurodegenerative disorders through the activation of specific targets within the so-called endocannabinoid system. The case of compounds targeting selectively the CB₂ receptor is particularly attractive because: (i) they are devoid of frequent psychoactive effects associated with the activation of the CB₁ receptor; and (ii) CB₂ receptors are significantly up-regulated in glial elements in neurodegenerative disorders. This fact has remained elusive in PD, although recent results have proven up-regulatory responses of glial CB₂ receptors in a few neurotoxin-based models of experimental PD. However, the issue remains to be studied in genetic models of this disorder.

Project Description:             
We have designed a research project aimed at confirming that CB₂ receptors are up-regulated in glial elements in a genetic model of PD, models with a mutation of LRRK2 gene, which is the most prevalent cause of familial PD. We will also study whether the pharmacological activation of this receptor with selective ligands may serve to delay disease progression in these models, and whether these potential benefits may involve the well-demonstrated effects of CB₂ receptors on glial influences to neurons, as has been demonstrated in a few neurotoxin-based models of experimental PD as well as in other neurodegenerative disorders.

Relevance to Diagnosis/Treatment of Parkinson’s Disease:                     
The present project may provide preclinical data that facilitate the development of a new disease-modifying therapy for PD, based on the activation of CB₂ receptors that are recruited at glial elements in lesioned structures during degenerative processes in this disorder. The activation of these receptors may play a positive role in normalizing the glial influence on neuronal survival.

Anticipated Outcome:          
We expect that our project may serve to extend the potential of CB₂ receptors as an anti-inflammatory and neuroprotective target: (i) from other neurodegenerative disorders to PD, and (ii) from neurotoxin-based models of this disorder to progressive genetic models of PD. We also expect to provide sufficient evidence of this potential that justifies the development of clinical studies with the available cannabinoid-based medicines targeting the CB₂ receptor in PD patients.