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Development of An Oral Treatment with the PPAR-γ-Acting Cannabinoid VCE-003.2 Against the Inflammation-Driven Neuronal Deterioration in Experimental Parkinson's Disease.

dc.contributor.authorBurgaz, Sonia
dc.contributor.authorGarcia, Concepcion
dc.contributor.authorGomez-Cañas, Maria
dc.contributor.authorMuñoz, Eduardo
dc.contributor.authorFernandez-Ruiz, Javier
dc.contributor.funderCIBERNED
dc.contributor.funderMINECO-Biomedicina
dc.contributor.funderMINECO
dc.date.accessioned2023-01-25T13:37:48Z
dc.date.available2023-01-25T13:37:48Z
dc.date.issued2019-07-22
dc.description.abstractIn a recent study, we described the neuroprotective properties of VCE-003.2-an aminoquinone derivative of the non-psychotropic phytocannabinoid cannabigerol (CBG)-administered intraperitoneally (i.p.) in an inflammatory model of Parkinson's disease (PD). We also demonstrated that these properties derive from its activity on the peroxisome proliferator-activated receptor-γ, in particular at a regulatory site within this receptor type. In the present study, we wanted to further confirm this neuroprotective potential using an oral lipid formulation of VCE-003.2, developed to facilitate the clinical development of this phytocannabinoid derivative. To this end, we evaluated VCE-003.2, administered orally at two doses (10 and 20 mg/kg), to mice subjected to unilateral intrastriatal injections of lipopolysaccharide (LPS), a classic model of inflammation-driven neuronal deterioration that recapitulates characteristics of PD. The administration of VCE-003.2 to these mice showed, as expected, poor activity in the different motor tests (rotarod, computer-aided actimeter) used in experimental parkinsonism, in general due to the lack of evident changes in these behaviors by LPS lesion. However, VCE-003.2, at 20 mg/kg, was highly active in improving the changes detected in LPS-lesioned mice in the cylinder rearing test. In addition, the histopathological analysis of the basal ganglia revealed a trend towards recovery at 20 mg/kg VCE-003.2 in the loss of tyrosine hydroxylase-containing nigrostriatal neurons, as well as a complete reduction in the elevated LAMP-1 immunolabeling (reflecting autophagy impairment) caused by LPS lesion. These effects were not seen at 10 mg/kg. This was associated with a partial reduction in the intense glial reactivity provoked by LPS in the substantia nigra, in particular the astroglial reactivity labeled with glial fibrillary acidic protein. The analysis using qPCR in the striatum of proinflammatory mediators, such as tumor necrosis factor-α, interleukin-1β, inducible nitric oxide synthase, and cyclooxygenase-2, showed that the marked elevations provoked by the LPS lesion tended to be, in general, attenuated by VCE-003.2 treatment, with the greatest effects normally found with the highest dose of 20 mg/kg. In summary, our data confirm the neuroprotective potential of an oral formulation of VCE-003.2 against neuronal injury in an in vivo model of PD based on neuroinflammation, and this study opens the possibility to further the development of oral VCE-003.2 in the clinic.
dc.description.versionSi
dc.identifier.citationBurgaz S, García C, Gómez-Cañas M, Muñoz E, Fernández-Ruiz J. Development of An Oral Treatment with the PPAR-γ-Acting Cannabinoid VCE-003.2 Against the Inflammation-Driven Neuronal Deterioration in Experimental Parkinson's Disease. Molecules. 2019 Jul 25;24(15):2702
dc.identifier.doi10.3390/molecules24152702
dc.identifier.essn1420-3049
dc.identifier.pmcPMC6696432
dc.identifier.pmid31349553
dc.identifier.pubmedURLhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC6696432/pdf
dc.identifier.unpaywallURLhttps://www.mdpi.com/1420-3049/24/15/2702/pdf
dc.identifier.urihttp://hdl.handle.net/10668/14314
dc.issue.number15
dc.journal.titleMolecules
dc.language.isoen
dc.organizationHospital Universitario Reina Sofía
dc.organizationInstituto Maimónides de Investigación Biomédica de Córdoba-IMIBIC
dc.page.number13
dc.publisherMDPI
dc.pubmedtypeJournal Article
dc.relation.projectIDCB06/05/0089
dc.relation.projectIDSAF2015-68580-C2-1
dc.relation.projectIDRRTC-2014-1877-1
dc.relation.publisherversionhttps://www.mdpi.com/1420-3049/24/15/2702
dc.rightsAttribution 4.0 International
dc.rights.accessRightsopen access
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/
dc.subjectPPAR-γ
dc.subjectParkinson’s disease
dc.subjectVCE-003.2
dc.subjectCannabinoids
dc.subjectInflammation
dc.subjectOral formulation
dc.subjectY receptors
dc.subject.decsAdministración oral
dc.subject.decsBiomarcadores
dc.subject.decsCannabinoides
dc.subject.decsCitocinas
dc.subject.decsInmunohistoquímica
dc.subject.decsMediadores de inflamación
dc.subject.decsModelos animales de enfermedad
dc.subject.meshAdministration, oral
dc.subject.meshAnimals
dc.subject.meshBiomarkers
dc.subject.meshCannabinoids
dc.subject.meshCytokines
dc.subject.meshDisease models, animal
dc.subject.meshFemale
dc.subject.meshImmunohistochemistry
dc.subject.meshInflammation mediators
dc.subject.meshMice
dc.subject.meshNeurons
dc.subject.meshNeuroprotective agents
dc.subject.meshPPAR gamma
dc.subject.meshParkinsonian disorders
dc.subject.meshQuinones
dc.subject.meshSubstantia nigra
dc.titleDevelopment of An Oral Treatment with the PPAR-γ-Acting Cannabinoid VCE-003.2 Against the Inflammation-Driven Neuronal Deterioration in Experimental Parkinson's Disease.
dc.typeresearch article
dc.type.hasVersionVoR
dc.volume.number24
dspace.entity.typePublication

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