Cannabidiol as a Therapeutic Target: Evidence of its Neuroprotective and Neuromodulatory Function in Parkinson’s Disease.
The chronic administration of l-DOPA leads to a sensitization of D1 receptors, which maintain the over-activation of PKA in LIDs. PKA regulates the pathway that activates DARPP-32, which inhibits the modification by PP-1, of ERK1/2 signaling, which acts on nuclear targets, such as MSK1, and, along with histone H3, regulates the expression of early genes such as c-fos and zif268. CBD exerts antidyskinetic effects by increasing AEA concentration by inhibiting of FAAH, thus stimulating the CB1 receptors, which decrease PKA activity. The CB1 requiere the co-administration of a TRPV1 inhibitor (CPZ), because they stimulate TRPV1 via AEA and CBD, both of which generate opposite effects to the activation of CB1. Furthermore, increased OEA is generated via the inhibition of FAAH, an endocannabinoid able to block TRPV1 and stimulate PPARσ receptors, reducing biochemical markers such as FosB and pAcH3. In addition, CBD activate the 5-HT1A receptor, a receptor that had previously only been implicated in the anticataleptic effect of CBD. By activating PPARγ receptors, CBD reduces the levels of molecular markers involved in LIDs, such as pERK, pAcH3, NF-Kβ and COX-2, while it also generates an anti-inflammatory effect by stimulating said receptors, which are present in the glia. Furthermore, CBD is able to reduce oxidative damage, decreasing the production of ROS by increasing the activity of mitochondrial complexes. The inverse agonism that CBD exerts on GPR6 could form part of its antidyskinetic mechanisms. Abbreviations: l-DOPA, L-3,4-Dihydroxyphenylalanine; D1, Dopamine receptor 1; PKA, cAMP-dependent protein kinase; LID, l-DOPA-induced dyskinesias; DARPP-32–32 KDa Phosphoprotein regulated by cAMP and dopamine; PP-1, phosphoprotein 1; ERK, extracellular signal-regulated kinase; MSK-1, mitogen and stress regulated protein kinase; CBD, cannabidiol; AEA, anandamide; FAAH, fatty acid amide hydrolase; TRPV1, transient potential receptor V1; CPZ, cpazazepine; OEA, oleoylethanolamide; PPARα, peroxisome proliferator activated receptor α; pAcH3, Histone 3 phosphoacetylation; 5HT1A, Serotonin receptor 1A; PPARγ, peroxisome proliferator activated receptor γ; NF-Kβ, nuclear factor Kβ; COX-2, cyclooxygenase 2.