Cannabidiol as a Therapeutic Target: Evidence of its Neuroprotective and Neuromodulatory Function in Parkinson’s Disease

Abstract

The phytocannabinoids of Cannabis sativa L. have, since ancient times, been proposed as a pharmacological alternative for treating various central nervous system (CNS) disorders. Interestingly, cannabinoid receptors (CBRs) are highly expressed in the basal ganglia (BG) circuit of both animals and humans. The BG are subcortical structures that regulate the initiation, execution, and orientation of movement. CBRs regulate dopaminergic transmission in the nigro-striatal pathway and, thus, the BG circuit also. The functioning of the BG is affected in pathologies related to movement disorders, especially those occurring in Parkinson’s disease (PD), which produces motor and non-motor symptoms that involving GABAergic, glutamatergic, and dopaminergic neural networks. To date, the most effective medication for PD is levodopa (l-DOPA); however, long-term levodopa treatment causes a type of long-term dyskinesias, l-DOPA-induced dyskinesias (LIDs). With neuromodulation offering a novel treatment strategy for PD patients, research has focused on the endocannabinoid system (ECS), as it participates in the physiological neuromodulation of the BG in order to control movement. CBRs have been shown to inhibit neurotransmitter release, while endocannabinoids (eCBs) play a key role in the synaptic regulation of the BG. In the past decade, cannabidiol (CBD), a non-psychotropic phytocannabinoid, has been shown to have compensatory effects both on the ECS and as a neuromodulator and neuroprotector in models such as 6-hydroxydopamine (6-OHDA), 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), and reserpine, as well as other PD models. Although the CBD-induced neuroprotection observed in animal models of PD has been attributed to the activation of the CB1 receptor, recent research conducted at a molecular level has proposed that CBD is capable of activating other receptors, such as CB2 and the TRPV-1 receptor, both of which are expressed in the dopaminergic neurons of the nigro-striatal pathway. These findings open new lines of scientific inquiry into the effects of CBD at the level of neural communication. Cannabidiol activates the PPARγ, GPR55, GPR3, GPR6, GPR12, and GPR18 receptors, causing a variety of biochemical, molecular, and behavioral effects due to the broad range of receptors it activates in the CNS. Given the low number of pharmacological treatment alternatives for PD currently available, the search for molecules with the therapeutic potential to improve neuronal communication is crucial. Therefore, the investigation of CBD and the mechanisms involved in its function is required in order to ascertain whether receptor activation could be a treatment alternative for both PD and LID.

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“…Marijuana has been used for 8000 years in India, China, and Middle East for fiber and medicinal properties; then introduced to Europe in early nineteenth century by Napoleon's army returning from Egypt and then to Britain for medical use by a surgeon who served in India. CBD is the non-psychotropic component of marijuana, and there are numerous therapeutic effects of this drug including treatment of anxiety, pain, nausea, and motor deficits including the tremor in Parkinson's disease [116]. CBD has both neuromodulatory and neuroprotective effects through a number of mechanisms including blocking neuroinflammation and potentiating anti-inflammatory pathways, improving mitochondrial function, GABA A agonist potentiation, stimulation of 5HT 1A receptors, and enhancing levels of anandamide (AEA) [116][117][118][119].…”

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“…Arachidonoylethanolamine, also known as anandamide (AEA), and 2-arachidonoyl-glycerol (2-AG) are the main representatives of eCBs. The endocannabinoid system (ECS) is described as a complex lipid network consisting of cannabinoid receptors (CBRs), endogenous ligands and the enzymes involved in endocannabinoid degradation and synthesis [ 31 , 32 ]. The ECS has been implicated as an important regulatory component by the regulation of the local CBF and by the maintenance of the BBB and related transport proteins [ 32 ].…”

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“…In those who experience medical-resistant tremor, worsening symptoms, and functional impairments when the medication wears off, treatments such as deep brain stimulation and levodopa-carbidopa enteral suspension could have benefits for them [95]. Nevertheless, levodopa treatment, which is currently considered the most effective medication for PD, causes a type of long-term dyskinesias, l-DOPA-induced dyskinesias (LIDs) [96]. Even if the aim of current treatments is to improve functional capacity of the patients, they are not able to modify the progression of the neurodegenerative process [97].…”

“…Consequently, it causes a variety of biochemical, molecular, and behavioral effects since there are a broad range of receptors being able to activate in the CNS. Thanks to these findings, a new line of scientific inquiry is opened into the effect of CBD at the neural communication level [99].…”