1.5.3 Parkinson’s disease
Parkinson’s disease is the second most prevalent neurodegenerative disease, affecting 5% of the population over 85 years of age. Furthermore, its global burden has more than doubled, making it the fastest growing neurodegenerative disease. Genetic causes also contribute to the etiology of Parkinson’s disease, but in smaller proportions, estimated at 5% of all people with the disease. It is known that the combination of these genetic and environmental factors increases the risk of the disease [150].
Symptomatically, it is characterized by motor and non-motor symptoms, which are generally underdiagnosed and untreated [149]; being diagnosed only with the development of motor impairment (e.g. tremor, rigidity and bradykinesia). However, motor features are strongly linked to dopaminergic damage in the nigrostriatal pathway, which occurs only in the intermediate stages of the disease [148]. Staging is based on the appearance of α-synuclein aggregates, and it can take 20 years for motor disorders to appear, highlighting the involvement of other neurotransmission systems and their relationship with early non-motor symptoms, such as mild olfactory and cognitive impairment and depression [149, 151].
Parkinson’s disease onset is tightly related to α-synuclein overexpression and/or modification, a protein involved in the synaptic vesicle release. In turn, misfolded α-synuclein forms aggregates called Lewy bodies [152]. Due to an impaired synaptic function, several cellular and physiological mechanisms are affected, resulting in neuroinflammation, oxidative stress, reduced trophic support, and excitotoxicity [153]. Since endocannabinoids regulate synaptic and motor functions through cannabinoid receptors CB1 and CB2, this system is also impacted by striatal rearrangement after dopamine depletion [154-156].
In fact, people with Parkinson’s disease have higher AEA levels and altered cannabinoid expression [156-158]. Regarding the CB1 receptor, brain MRI studies demonstrated greater expression in the mesolimbic and mesocortical regions [158, 159]. In contrast, the availability of CB1 and CB2 receptors decreased in the substantia nigra [157, 158]; furthermore, the CB1 receptor appears to be involved in the action of 3,4-dihydroxy-L-phenylalanine (L-DOPA), preventing motor fluctuations that are commonly observed in therapy [160], and the CB2 receptor is increased in glial cells in post-mortem tissues [161].
Based on exposure, pharmacological modulation of the ES may be an interesting approach for Parkinson’s disease management. In vitro and in vivo studies on THC effects on Parkinson’s disease models have revealed neuroprotective effects that are likely mediated by the CB1 receptor [162-165]. Furthermore, PPARγ appears to play a crucial role, mediating the downregulation of the CB1 receptor and the restoration of mitochondrial content [162, 166, 167].
Recently, in a meta-analysis, it was shown that treatment with CBD promoted a significant improvement in parkinsonian symptoms, however, these benefits were not seen in therapy with nabilone [113]. Thus, modulation between cannabinoid receptors and TRPV may be associated with these results [126, 168, 169].
Beneficial effects of CBD in Parkinson’s disease models suggest CB2 but not CB1 receptor involvement [170, 171]. CBD treatment showed neuroprotective effects on the nigrostriatal pathway [163, 170, 172, 173], in vitro data suggest that CBD’s neuroprotective action is linked to tropomyosin receptor kinase A activation [174]. Lastly, Gugliandolo et al. [171] reported that the antiapoptotic effect of CBD is mediated by ERK and Akt/mTOR pathways, while ERK activation seemed to be modulated by TRPV1 and CB2 receptors. Finally, recently, Wang et al [175] demonstrated anti-apoptotic effects of dopaminergic neurons and neuroinflammation in which CBD repressed the expression of the inflammasome pathway NLRP3/caspase-1/IL-1β, upregulated Bcl-2 and downregulated Bax and Caspase-3, corroborating its neuroprotective and anti-apoptotic role.
Besides THC and CBD, other cannabis derivatives displayed therapeutic potential in preclinical investigations. There is evidence that THCA, 7 (Z)-methyl p-hydroxycinnamate (ZMHC), Beta-caryophyllene (BCP), and THCV have neuroprotective effects in Parkinson’s disease models [165, 172, 173, 176]. Moreover, BCP chronic treatment demonstrated antioxidant and anti-inflammatory effects mediated by the CB2 receptor in a Parkinson’s disease model induced by rotenone [176, 177]. In turn, THCV inhibits motor impairment, glutamatergic changes, and microglial activation induced by6-hydroxydopamine (6-OHDA)[172].
In summary, the scientific evidence on therapeutic cannabis use and its derivatives in Parkinson’s disease are inconsistent and of poor quality, hindering concrete conclusions of its efficacy to be made. Based on the scientific evidence presented in this review, the therapeutic potential of phytocannabinoids in Parkinson’s disease is illustrated in figure 4 and the studies shown in table 3.
Fig. 4. Diagram of interactions and therapeutic potential of phytocannabinoids in Parkinson’s disease.
Table 3. Preclinical and clinical evidence using Cannabis derivatives in in Parkinson’s disease models and patients