Co-administration of cannabidiol and capsazepine reduces L-DOPA-induced dyskinesia in mice: Possible mechanism of action

Abstract

Pharmacological manipulation of the endocannabinoid system represents a promising therapy to alleviate L-3,4-dihydroxyphenylalanine (L-DOPA)-induced dyskinesia (LID) in Parkinson's disease (PD). Our aim was to verify whether cannabidiol (CBD), the major non-psychoactive constituent of Cannabis sativa, modifies LID. To this end, the present study employed the 6-hydroxydopamine-neurotoxin model in male C57⁄BL6 mice to reproduce the pattern of cell death present in PD patients. Unilateral striatal lesioned mice received L-DOPA for 21days, developing severe axial, limb, locomotor and orofacial abnormal involuntary movements (AIMs). Following that, the animals were treated with CBD (intraperitoneally) before L-DOPA for three days, alone or in combination with antagonists of the Transient Receptor Potential Vanniloid-1 (TRPV-1), cannabinoid type 1 (CB1) or Peroxisome Proliferator-Activated type gamma (PPARγ) receptors. Nor CBD or any of the antagonists individually were effective in decreasing AIMs. CBD administered with the TRPV-1 antagonist capsazepine (CPZ) reduced AIMs. Treatment with arachidonoyl-serotonin (AA-5-HT), an inhibitor of the enzyme responsible for anandamide metabolism fatty acid amide hydrolase (FAAH) and a TRPV-1 blocker, reproduced these findings. The CB1 receptor antagonist AM251 or the PPARγ receptor antagonist GW9662 selectively reversed the antidyskinetic effect of CPZ+CBD, with AM251 decreasing limb and orofacial AIMs and GW9662 reducing axial AIMs. The decrease of LID by CPZ+CBD was associated with a reduction in the molecular markers phospho-acetylated histone H3 and phosphorylated extracellular signal-regulated protein kinases 1 and 2. L-DOPA treatment in hemiparkinsonian mice increased the pro-inflammatory markers cyclooxygenase-2 and nuclear factor-kappa B in the lesioned striatum. These markers were also decreased by CPZ+CBD treatment. Our study indicates that CBD, together with a TRPV-1 antagonist, reduces LID by acting on CB1 and PPARγ receptors and reducing the expression of the inflammatory markers cyclooxygenase-2 and nuclear factor-kappa B.