“Cannabidivarin (CBDV), a structural analog of cannabidiol (CBD), has received attention in recent years owing to its anticonvulsant property and potential for treating autism spectrum disorder. However, the function and mechanism of CBDV involved in the progression of Parkinson’s disease (PD) remain unclear. In this work, we found that CBDV inhibited α-synuclein (α-syn) aggregation in an established transgenetic Caenorhabditis elegans (C. elegans). The phenolic hydroxyl groups of CBDV are critical for scavenging reactive oxygen species (ROS), reducing the in vivo aggregation of α-syn and preventing DAergic neurons from 6-hydroxydopamine (6-OHDA)-induced injury and degeneration. By combining multiple biophysical approaches, including nuclear magnetic resonance spectrometry, transmission electron microscopy and fibrillation kinetics assays, we confirmed that CBDV does not directly interact with α-syn or inhibit the formation of α-syn fibrils in vitro. Further cellular signaling investigation showed that the ability of CBDV to prevent oxidative stress, the accumulation of α-syn and the degeneration of DAergic neurons was mediated by DAF-16 in the worms. This study demonstrates that CBDV alleviates the aggregation of α-syn in vivo and reveals that the phenolic hydroxyl groups of CBDV are critical for this activity, providing a potential for the development of CBDV as a drug candidate for PD therapeutics.”

https://pubmed.ncbi.nlm.nih.gov/36583706/

https://faseb.onlinelibrary.wiley.com/doi/10.1096/fj.202200278RR

“Medicinal cannabis has shown promise for the symptomatic treatment of Parkinson’s disease (PD), but patient exposure to whole plant mixtures may be undesirable due to concerns around safety, consistency, regulatory issues, and psychoactivity. Identification of a subset of components responsible for the potential therapeutic effects within cannabis represents a direct path forward for the generation of anti-PD drugs. Using an in silico database, literature reviews, and cell based assays, GB Sciences previously identified and patented a subset of five cannabinoids and five terpenes that could potentially recapitulate the anti-PD attributes of cannabis. While this work represents a critical step towards harnessing the anti-PD capabilities of cannabis, polypharmaceutical drugs of this complexity may not be feasible as therapeutics. In this paper, we utilize a reductionist approach to identify minimal essential mixtures (MEMs) of these components that are amenable to pharmacological formulation. In the first phase, cell-based models revealed that the cannabinoids had the most significant positive effects on neuroprotection and dopamine secretion. We then evaluated the ability of combinations of these cannabinoids to ameliorate a 6-hydroxydopmamine (OHDA)-induced change in locomotion in larval zebrafish, which has become a well-established PD disease model. Equimolar mixtures that each contained three cannabinoids were able to significantly reverse the OHDA mediated changes in locomotion and other advanced metrics of behavior. Additional screening of sixty-three variations of the original cannabinoid mixtures identified five highly efficacious mixtures that outperformed the original equimolar cannabinoid MEMs and represent the most attractive candidates for therapeutic development. This work highlights the strength of the reductionist approach for the development of ratio-controlled, cannabis mixture-based therapeutics for the treatment of Parkinson’s disease.”

https://pubmed.ncbi.nlm.nih.gov/36278152/

“Cannabis has therapeutic promise in PD. However, there is a need to move beyond whole plant extracts and generate safe, reproducible medicines for patients. This paper identified promising minimal essential mixtures of cannabinoids based on a step-wise, strategic approach to reducing the complexity of the plant secondary metabolome. The sequential use of in silico, in vitro, and medium throughput in vivo experimental systems has generated refined, de-risked, mixtures that can now be tested in additional, higher-cost, preclinical model systems of PD.”

https://www.frontiersin.org/articles/10.3389/fphar.2022.907579/full

“Cannabidiol (CBD) presents antiparkinsonian properties and neuromodulatory effects, possibly due to the pleiotropic activity caused at multiple molecular targets.

Recently, the GPR55 receptor has emerged as a molecular target of CBD. Interestingly, GPR55 mRNA is expressed in the external globus pallidus (GPe) and striatum, hence, it has been suggested that its activity is linked to motor dysfunction in Parkinson’s disease (PD).

The present study aimed to evaluate the effect of the intrapallidal injection of both CBD and a selective GPR55 antagonist (CID16020046) on motor asymmetry, fine motor skills, and GAD-67 expression in hemiparkinsonian rats. The hemiparkinsonian animal model applied involved the induction of a lesion in male Wistar rats via the infusion of the neurotoxin 6-hydroxydopamine (6-OHDA) into the medial forebrain bundle via stereotaxic surgery. After a period of twenty days, a second surgical procedure was performed to implant a guide cannula into the GPe. Seven days later, lysophosphatidylinositol (LPI), CBD, or CID16020046 were injected once a day for three consecutive days (from the 28th to the 30th day post-lesion). Amphetamine-induced turning behavior was evaluated on the 14th and 30th days post-injury. The staircase test and fine motor skills were evaluated as follows: the rats were subject to a ten-day training period prior to the 6-OHDA injury; from the 15th to the 19th days post-lesion, the motor skills alterations were evaluated under basal conditions; and, from the 28th to the 30th day post-lesion, the pharmacological effects of the drugs administered were evaluated.

The results obtained show that the administration of LPI or CBD generated lower levels of motor asymmetry in the turning behavior of hemiparkinsonian rats. It was also found that the injection of CBD or CID16020046, but not LPI, in the hemiparkinsonian rats generated significantly superior performance in the staircase test, in terms of the use of the forelimb contralateral to the 6-OHDA-induced lesion, when evaluated from the 28th to the 30th day post-lesion. Similar results were also observed for superior fine motor skills performance for pronation, grasp, and supination. Finally, the immunoreactivity levels were found to decrease for the GAD-67 enzyme in the striatum and the ipsilateral GPe of the rats injected with CBD and CID16020046, in contrast with those lesioned with 6-OHDA.

The results obtained suggest that the inhibitory effects of CBD and CID16020046 on GPR55 in the GPe could be related to GABAergic overactivation in hemiparkinsonism, thus opening new perspectives to explain, at a cellular level, the reversal of the motor impairment observed in PD models.”

https://pubmed.ncbi.nlm.nih.gov/36120297/

https://www.frontiersin.org/articles/10.3389/fphar.2022.945836/full

“Parkinson disease (PD) is the second most progressive neurodegenerative disorder of the central nervous system (CNS) in the elderly, causing motor impediments and cognitive dysfunctions. Dopaminergic (DA) neuron degeneration and α-synuclein (α-Syn) accumulation in substantia nigra pars compacta (SNPc) are the major contributor to this disease. At present, the disease has no effective treatment. Many recent studies focus on identifying novel therapeutics that provide benefits to stop disease advancement in PD patients.

Cannabidiol (CBD) is a cannabinoid derived from the Cannabis Sativa plant and possesses anti-depressive, anti-inflammatory, and antioxidative effects. The present study aims to evaluate the neuroprotective effect of CBD in transgenic C. elegans PD models.

We observed that CBD at 0.025mM (24.66%), 0.05mM (52.41%) and 0.1mM (71.36%) diminished DA neuron degenerations induced by 6-hydroxydopamine (6-OHDA), reduced (0.025, 27.1%), (0.05, 38.9%), (0.1, 51.3%) food-sensing behavioural disabilities in BZ555, reduced 40.6%, 56.3%, 70.2% the aggregative toxicity of α-Syn and expanded the nematodes’ lifespan up to 11.5%, 23.1%, 28.8%, dose-dependently. Moreover, CBD augmented the ubiquitin-like proteasomes 28.11%, 43.27, 61.33% and SOD-3 expressions by about 16.4%, 21.2%, 44.8% in transgenic models. Further, we observed the antioxidative role of CBD by reducing 33.2%, 41.4%, 56.7% reactive oxygen species in 6-OHDA intoxicated worms.

Together, these findings supported CBD as an anti-parkinsonian drug and may exert its effects by raising lipid depositions to enhance proteasome activity and reduce oxidative stress via the antioxidative pathway.”

https://pubmed.ncbi.nlm.nih.gov/36108815/

“CBD neuroprotective effects were assessed in pharmacological transgenic models of PD. According to our assessment, CBD promoted neuroprotection via recovery of degenerated DA neurons in 6-OHDA-exposed C. elegans and significantly reduced the α-Syn accumulations. Furthermore, CBD enhanced the lipid depositions, ubiquitin-like proteasome activities, food sensing behavior, and lifespan in the treated animals. CBD could restrain PD patients’ inflammations and decline DA neuron damage via leading.”

https://www.sciencedirect.com/science/article/abs/pii/S0161813X22001462?via%3Dihub