VCE-003.2, a novel cannabigerol derivative, enhances neuronal progenitor cell survival and alleviates symptomatology in murine models of Huntington's disease

Javier Díaz-Alonso, Juan Paraíso-Luna, Carmen Navarrete, Carmen Del Río, Irene Cantarero, Belén Palomares, José Aguareles, Javier Fernández-Ruiz, María Luz Bellido, Federica Pollastro, Giovanni Appendino, Marco A. Calzado, Ismael Galve-Roperh, Eduardo Muñoz

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Abstract

Cannabinoids have shown to exert neuroprotective actions in animal models by acting at different targets including canonical cannabinoid receptors and PPAR 3. We previously showed that VCE-003, a cannabigerol (CBG) quinone derivative, is a novel neuroprotective and anti-inflammatory cannabinoid acting through PPAR 3. We have now generated a non-thiophilic VCE-003 derivative named VCE-003.2 that preserves the ability to activate PPAR 3 and analyzed its neuroprotective activity. This compound exerted a prosurvival action in progenitor cells during neuronal differentiation, which was prevented by a PPAR 3 antagonist, without affecting neural progenitor cell proliferation. In addition, VCE-003.2 attenuated quinolinic acid (QA)-induced cell death and caspase-3 activation and also reduced mutant huntingtin aggregates in striatal cells. The neuroprotective profile of VCE-003.2 was analyzed using in vivo models of striatal neurodegeneration induced by QA and 3-nitropropionic acid (3NP) administration. VCE-003.2 prevented medium spiny DARPP32 + neuronal loss in these Huntington's-like disease mice models improving motor deficits, reactive astrogliosis and microglial activation. In the 3NP model VCE-003.2 inhibited the upregulation of proinflammatory markers and improved antioxidant defenses in the brain. These data lead us to consider VCE-003.2 to have high potential for the treatment of Huntington's disease (HD) and other neurodegenerative diseases with neuroinflammatory traits.

Lingua originaleInglese
Numero di articolo29789
RivistaScientific Reports
Volume6
DOI
Stato di pubblicazionePubblicato - 19 lug 2016

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