The action of cannabinoid drugs in L-DOPA-induced DISCINESIA: analysis of neuroinf...
| Full text | |
| Author(s): |
dos-Santos-Pereira, Mauricio
;
da-Silva, Celia Aparecida
;
Guimaraes, Francisco Silveira
;
Del-Bel, Elaine
Total Authors: 4
|
| Document type: | Journal article |
| Source: | Neurobiology of Disease; v. 94, p. 179-195, OCT 2016. |
| Web of Science Citations: | 18 |
| 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 21 days, 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 (PPAR gamma) 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 PPAR gamma 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 PPAR gamma receptors and reducing the expression of the inflammatory markers cyclooxygenase-2 and nuclear factor-kappa B. (C) 2016 Published by Elsevier Inc. (AU) | |
| FAPESP's process: | 12/17626-7 - Cellular and molecular mechanisms involved in the role of atypical neurotransmitters in neuropsychiatric disorders |
| Grantee: | Francisco Silveira Guimaraes |
| Support type: | Research Projects - Thematic Grants |