Promising cannabinoid-based therapies for Parkinson's disease: motor symptoms to neuroprotection

Sandeep Vasant More, Dong-Kug Choi, Sandeep Vasant More, Dong-Kug Choi

Abstract

Parkinson's disease (PD) is a slow insidious neurological disorder characterized by a loss of dopaminergic neurons in the midbrain. Although several recent preclinical advances have proposed to treat PD, there is hardly any clinically proved new therapeutic for its cure. Increasing evidence suggests a prominent modulatory function of the cannabinoid signaling system in the basal ganglia. Hence, use of cannabinoids as a new therapeutic target has been recommended as a promising therapy for PD. The elements of the endocannabinoid system are highly expressed in the neural circuit of basal ganglia wherein they bidirectionally interact with dopaminergic, glutamatergic, and GABAergic signaling systems. As the cannabinoid signaling system undergoes a biphasic pattern of change during progression of PD, it explains the motor inhibition typically observed in patients with PD. Cannabinoid agonists such as WIN-55,212-2 have been demonstrated experimentally as neuroprotective agents in PD, with respect to their ability to suppress excitotoxicity, glial activation, and oxidative injury that causes degeneration of dopaminergic neurons. Additional benefits provided by cannabinoid related compounds including CE-178253, oleoylethanolamide, nabilone and HU-210 have been reported to possess efficacy against bradykinesia and levodopa-induced dyskinesia in PD. Despite promising preclinical studies for PD, use of cannabinoids has not been studied extensively at the clinical level. In this review, we reassess the existing evidence suggesting involvement of the endocannabinoid system in the cause, symptomatology, and treatment of PD. We will try to identify future threads of research that will help in the understanding of the potential therapeutic benefits of the cannabinoid system for treating PD.

Figures

Figure 1
Figure 1
Basal ganglial circuitry in Parkinson’s disease (PD) and tentative cannabinoid targets to improve motor disability in PD. Progressive loss of dopaminergic innervation in PD causes overactivity of the indirect (inhibitory) pathway, resulting in excess glutamatergic drive to the GPi and SNpr and diminished activity of the inhibitory GABAergic direct pathway, further disinhibiting the activity of the GPi and SNpr. As output nuclei (GPi and SNpr) use the inhibitory neurotransmitter GABA, this amplified basal ganglia output leads to extreme inhibition of the motor thalamus which acts as a “brake” on motor activity; thus, resulting in the onset of parkinsonian syndrome. The neural circuitry above depicts various possible cannabinoid- based targets (CB1, CB2, and TRPV1 receptors) that can be used to mitigate the symptoms observed in PD. Abbreviations: CB1, cannabinoid receptor 1; TRPV1, transient receptor potential vanilloid 1; GPe, external segment of the globus pallidus; GPi, internal segment of the globus pallidus; SNpc, substantia nigra pars compacta; SNpr, substantia nigra pars reticulata; STN, subthalamic nucleus; GABA, gamma-aminobutyric acid.
Figure 2
Figure 2
Probable mechanisms to describe the neuroprotective (independent of the CB1 receptor) action of cannabinoids in PD. Abbreviations: CB1, cannabinoid receptor 1; CB2, cannabinoid receptor 2; BDNF, Brain derived neurotrophic factor; ECBs, Endocannabinoids; ROS, reactive oxygen species; SOD, superoxide dismutase; NrF2, nuclear factor erythroid 2-related factor 2; NFκB, nuclear factor kappa-B; p38, p38 mitogen-activated protein kinases; iNOS, inducible nitric oxide synthase; COX-2, cyclooxygenase-2; TGF-β, transforming growth factor beta.

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