4'-fluorocannabidiol associated with capsazepine restrains L-DOPA-induced dyskinesia in hemiparkinsonian mice: Contribution of anti-inflammatory and anti-glutamatergic mechanisms.

Autor: Dos Santos Pereira M; Department of Basic and Oral Biology, FORP, Campus USP, University of São Paulo, Ribeirão Preto, Brazil; Paris Brain Institute, Inserm, CNRS, Sorbonne Université, Paris, France. Electronic address: msp_biomed@yahoo.com.br., Dias de Abreu GH; Department of Psychological and Brain Sciences, Program in Neuroscience, Gill Center for Bimolecular Sciences, Indiana University, Bloomington, United States. Electronic address: gdiasdea@iu.edu., Vanderlei LCA; Department of Basic and Oral Biology, FORP, Campus USP, University of São Paulo, Ribeirão Preto, Brazil. Electronic address: leonardo.calaca@usp.br., Raisman-Vozari R; Paris Brain Institute, Inserm, CNRS, Sorbonne Université, Paris, France. Electronic address: ritaraisman@gmail.com., Guimarães FS; Department of Pharmacology, FMRP, Campus USP, University of São Paulo, Ribeirão Preto, Brazil. Electronic address: fsguimar@fmrp.usp.br., Lu HC; Department of Psychological and Brain Sciences, Program in Neuroscience, Gill Center for Bimolecular Sciences, Indiana University, Bloomington, United States. Electronic address: hclu@indiana.edu., Michel PP; Paris Brain Institute, Inserm, CNRS, Sorbonne Université, Paris, France. Electronic address: patrick.michel@icm-institute.org., Del Bel E; Department of Basic and Oral Biology, FORP, Campus USP, University of São Paulo, Ribeirão Preto, Brazil. Electronic address: eadelbel@usp.br.
Jazyk: angličtina
Zdroj: Neuropharmacology [Neuropharmacology] 2024 Jun 15; Vol. 251, pp. 109926. Date of Electronic Publication: 2024 Mar 28.
DOI: 10.1016/j.neuropharm.2024.109926
Abstrakt: We tested the efficacy of 4'-fluorocannabidiol (4'-F-CBD), a semisynthetic cannabidiol derivative, and HU-910, a cannabinoid receptor 2 (CB2) agonist in resolving l-DOPA-induced dyskinesia (LID). Specifically, we were interested in studying whether these compounds could restrain striatal inflammatory responses and rescue glutamatergic disturbances characteristic of the dyskinetic state. C57BL/6 mice were rendered hemiparkinsonian by unilateral striatal lesioning with 6-OHDA. Abnormal involuntary movements were then induced by repeated i.p. injections of l-DOPA + benserazide. After LID was installed, the effects of a 3-day treatment with 4'-F-CBD or HU-910 in combination or not with the TRPV1 antagonist capsazepine (CPZ) or CB2 agonists HU-308 and JWH015 were assessed. Immunostaining was conducted to investigate the impacts of 4'-F-CBD and HU-910 (with CPZ) on inflammation and glutamatergic synapses. Our results showed that the combination of 4'-F-CBD + CPZ, but not when administered alone, decreased LID. Neither HU-910 alone nor HU-910+CPZ were effective. The CB2 agonists HU-308 and JWH015 were also ineffective in decreasing LID. Both combination treatments efficiently reduced microglial and astrocyte activation in the dorsal striatum of dyskinetic mice. However, only 4'-F-CBD + CPZ normalized the density of glutamate vesicular transporter-1 (vGluT1) puncta colocalized with the postsynaptic density marker PSD95. These findings suggest that 4'-F-CBD + CPZ normalizes dysregulated cortico-striatal glutamatergic inputs, which could be involved in their anti-dyskinetic effects. Although it is not possible to rule out the involvement of anti-inflammatory mechanisms, the decrease in striatal neuroinflammation markers by 4'-F-CBD and HU-910 without an associated reduction in LID indicates that they are insufficient per se to prevent LID manifestations.
Competing Interests: Declaration of competing interest Francisco S. Guimarães is a co-inventor of the patent “Fluorinated CBD compounds, compositions and uses thereof. Pub. No.: WO/2014/108899. International Application No.: PCT/IL 2014/050023″ Def. US no. Reg. 62193296; July 29, 2015; INPI on August 19, 2015 (BR1120150164927). The University of São Paulo has licensed the patent to Phytecs Pharm (USP Resolution No. 15.1.130002.1.1). The University of São Paulo has an agreement with Prati-Donaduzzi (Toledo, Brazil) to “develop a pharmaceutical product containing synthetic cannabidiol and prove its safety and therapeutic efficacy in the treatment of epilepsy, schizophrenia, Parkinson's disease, and anxiety disorders.” The other authors declare no competing interests.
(Copyright © 2024 Elsevier Ltd. All rights reserved.)
Databáze: MEDLINE
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