摘要
Background:The administration of certain cannabinoids provides neuroprotection in models of neurodegenerative diseases by acting through various cellular and molecular mechanisms.Many cannabinoid actions in the nervous system are mediated by CB1 receptors,which can elicit psychotropic effects,but other targets devoid of psychotropic activity,including CB2 and nuclear PPARγreceptors,can also be the target of specific cannabinoids.Methods:We investigated the pro-neurogenic potential of the synthetic cannabigerol derivative,VCE-003.2,in striatal neurodegeneration by using adeno-associated viral expression of mutant huntingtin in vivo and mouse embryonic stem cell differentiation in vitro.Results:Oral administration of VCE-003.2 protected striatal medium spiny neurons from mutant huntingtin-induced damage,attenuated neuroinflammation and improved motor performance.VCE-003.2 bioavailability was characterized and the potential undesired side effects were evaluated by analyzing hepatotoxicity after chronic treatment.VCE-003.2 promoted subventricular zone progenitor mobilization,increased doublecortin-positive migrating neuroblasts towards the injured area,and enhanced effective neurogenesis.Moreover,we demonstrated the proneurogenic activity of VCE-003.2 in embryonic stem cells.VCE-003.2 was able to increase neuroblast formation and striatal-like CTIP2-mediated neurogenesis.Conclusions:The cannabigerol derivative VCE-003.2 improves subventricular zone-derived neurogenesis in response to mutant huntingtin-induced neurodegeneration,and is neuroprotective by oral administration.
基金
This work was supported by the MINECO grant RTC-2015-3364 to EM and IGR cofounded by the European Development Regional Fund in the Framework of the Operative Program“Reinforcement of research,technological development and innovation”
IGR was also supported by grant PI15-00310 and PI18-00941 cofinanced by the European Development Regional Fund“A way to achieve Europe”
EM by the MINECO grant SAF2017-87701-R
JA and JPL were supported by FPI and FPU program fellowship(Ministerio de Educación,Cultura y Deporte)and DGR by Fundación Tatiana de Guzmán el Bueno.BP is a predoctoral fellow supported by the i-PFIS program,Instituto de Salud CarlosⅢ(IFI15/00022,European Social Fund“Investing in your future”).
