Abstract
BackgroundThe 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 PPARγ receptors, can also be the target of specific cannabinoids.MethodsWe 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.ResultsOral 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.ConclusionsThe cannabigerol derivative VCE-003.2 improves subventricular zone-derived neurogenesis in response to mutant huntingtin-induced neurodegeneration, and is neuroprotective by oral administration.
Highlights
The administration of certain cannabinoids provides neuroprotection in models of neurodegenerative diseases by acting through various cellular and molecular mechanisms
Huntington’s disease (HD) neurodegeneration occurs in adult brain, mutant htt expression is known to interfere with normal neurodevelopment at several levels
Mutant huntingtin alters the mode of division of subventricular zone (SVZ) progenitors by influencing mitotic spindle orientation, that in turn controls asymmetric cell division and neurogenesis [4]
Summary
The administration of certain cannabinoids provides neuroprotection in models of neurodegenerative diseases by acting through various cellular and molecular mechanisms. Mutant htt expression induces striatal atrophy and medium spiny neuron (MSN) death, which is responsible for the characteristic motor symptoms of the disease. HD neurodegeneration occurs in adult brain, mutant htt expression is known to interfere with normal neurodevelopment at several levels. Mutant huntingtin interferes with the activity of various transcription factors (GSX2+, ASCL1+, ISLT1+, NKX2.1) that are essential in controlling cortical and striatal neurogenesis [2, 3]. Mutant huntingtin decreases NeuroD1 activity, a transcription factor that acts as a major confluence node of different neurodevelopmental gene pathways [3]. Mutant huntingtin expression interferes with projection neuron migration as normal huntingtin regulates Rab11-mediated N-cadherin trafficking [5]
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