Roles of the Cannabinoid System in the Basal Ganglia in Parkinson’s Disease

Abstract

Parkinson’s disease (PD) is a neurodegenerative disease usually caused by neuroinflammation, oxidative stress and other etiologies. Recent studies have found that the cannabinoid system present in the basal ganglia has a strong influence on the progression of PD. Altering the cannabinoid receptor activation status by modulating endogenous cannabinoid (eCB) levels can exert an anti-movement disorder effect. Therefore, the development of drugs that modulate the endocannabinoid system may be a novel strategy for the treatment of PD. However, eCB regulation is complex, with diverse cannabinoid receptor functions and the presence of dopaminergic, glutamatergic, and γ-aminobutyric signals interacting with cannabinoid signaling in the basal ganglia region. Therefore, the study of eCB is challenging. Here, we have described the function of the cannabinoid system in the basal ganglia and its association with PD in three parts (eCBs, cannabinoid receptors, and factors regulating the cannabinoid metabolism) and summarized the mechanisms of action related to the cannabinoid analogs currently aimed at treating PD. The shortcomings identified from previous studies and the directions that should be explored in the future will provide insights into new approaches and ideas for the future development of cannabinoid-based drugs and the treatment of PD.

Commentary: Roles of the Cannabinoid System in the Basal Ganglia in Parkinson's Disease

“…The authors of the article support the notion that CB1 activation reduces excitotoxicity and promotes neural regeneration, suggesting a possible neuroprotective role in PD based on animal models and cell cultures studies (Wang et al, 2022 ), however, there are no clinical studies on patients with PD confirming that notion.…”

“…Regarding the effects of CB1 on neurotransmission, enhanced CB1 receptor transmission in the striatum and in the output ganglia of globus pallidus (GP) internus/substantia nigra pars reticulata may alleviate PD symptoms, whereas if CB1 is activated in GP externus, it exacerbates PD symptoms (Wang et al, 2022 ). This dual mechanism may explain why a CB1 antagonist (SR 141716) could not improve the severity of motor symptoms and levodopa-induced dyskinesia (LID) measured with UPDRS III and IV in an exploratory randomized, double-blind, placebo-controlled (RCT) study on 24 patients with PD (Mesnage et al, 2004 ).…”

“…Furthermore, the interaction between CB1 and dopamine receptors is justified presented as complex. The authors mentioned that CB1 receptor activation can antagonize the effect of dopamine receptor agonists on the one hand, yet may also act as a downstream effector of D2 receptors, on the other hand (Wang et al, 2022 ), which makes the expected clinical outcome unclear regarding the possible activation or inhibition of CB1 on PD symptoms, as well as on the response and side effects of dopamine agonists in patients with PD receiving cannabinoids as medication. This may also explain why both the CB1 agonist and antagonist may have been involved with LID.…”

“…This may also explain why both the CB1 agonist and antagonist may have been involved with LID. Indeed, the authors also referred that in the interaction between CB1 and D1, D2 receptors can modulate the LID (Wang et al, 2022 ), but the exact mechanism is still not understood, which is reflected in the fact that experimental and clinical trials reveal contradicting results (Sieradzan et al, 2001 ; Carroll et al, 2004 ; Chagas et al, 2014 ). Additionally, the relevance of the TRPV1 receptor as a new therapeutic target against LID is still not clearly understood and the experimental results, including the interaction with CB1, also remain controversial.…”

“…The main components of the endogenous cannabinoid system (ECS) are the following: (1) the endogenous cannabinoids (eCBs), (2) the cannabinoid receptors, i.e., CB1 and CB2, transient receptor potential vanilloid-1 (TRPV-1), G protein receptor-55 (GPR55), and peroxisome proliferator-activated receptors (PPARs), and (3) various enzymes responsible for the metabolism of cannabinoids, i.e., fatty acid amide hydrolase (FAAH) monoacylglycerol lipase (MAGL). These components are presented regarding their distribution and possible function in the basal ganglia and their pathways (Wang et al, 2022 ).…”