VCE 003.2, a novel cannabigerol derivative, enhances neuronal progenitor cell survival and alleviates symptomatology in murine models of Huntington's disease
Cannabinoids have shown to exert neuroprotective actions in animal models by acting at different targets including canonical cannabinoid receptors and PPARg. We previously showed that VCE 003, a cannabigerol (CBG) quinone derivative, is a novel neuroprotective and anti inflammatory cannabinoid acting through PPARg. We have now generated a non thiophilic VCE 003 derivative named VCE 003.2 that preserves the ability to activate PPARg and analyzed its neuroprotective activity. This compound exerted a prosurvival action in progenitor cells during neuronal differentiation, which was prevented by a PPARg 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.
Scientific reports