Investigating the potential of targeting the CB2 receptor for anti-inflammatory disease modification in Parkinson’s disease

Parkinson’s disease is a multifaceted neurodegenerative disorder that currently has no cure. Chronic neuroinflammation is thought to play a crucial role in the progression of the disease, with neuroinflammation and neurotoxicity driving each other in a self-sustaining cycle that is detrimental to the survival of the neurons. Subsequently, the concept of anti-inflammatory disease therapy for the treatment of Parkinson’s disease has emerged in recent years. The cannabinoid CB2 receptor is an attractive target for anti-neuroinflammatory therapy due to its location on microglia and its immunomodulatory effect on these cells. Thus, the overarching aim of this body of research was to investigate the potential of targeting the CB2 receptor for Parkinson’s disease therapy. Firstly, we assessed the temporal expression of the CB2 receptor in a genetic model of Parkinson’s disease that was induced by administering an adeno-associated viral (AAV) vector which expressed human α-synuclein with the A53T mutation to the rat brain. Following on from this, we endeavoured to enhance the AAV-α-synuclein model using a small molecule α-synuclein aggregator to aid in further studies of the condition. Finally, we investigated the potential of targeting the CB2 receptor for anti-inflammatory disease modification by determining if the pharmacological targeting of this receptor could provide functional neuroprotection in inflammatory rat models. In the AAV-α-synuclein genetic model of Parkinson’s disease, we did not detect any alterations in CB2 gene expression despite a profound upregulation in human α-synuclein expression in the substantia nigra and the striatum. However, there was a decrease in the striatal levels of the endocannabinoid 2-arachidonylglycerol (2-AG) and of the related N-acylethanolamine N-oleoyl ethanolamide (OEA), indicating a dysregulation of the cannabinoid system in this model. Interestingly, an overall decrease in the expression of microglial and astrocytic markers was observed in the substantia nigra, but these ...