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