Not just nociception: regulation of postnatal neurogenesis by TRPV1

The Endocannabinoid System has been shown to play a pivotal role in different neurogenic stages, namely in differentiation and maturation of postnatal neural stem/progenitor cells (NSPC) mainly via the activation of the classical cannabinoid receptors. Herein, we aimed at unravelling the role of cannabidivarin (CBDV), a non-psychotomimetic cannabinoid, with high affinity for the non-classical cannabinoid receptor vanilloid receptor 1 (TRPV1), on subventricular zone (SVZ) postnatal neurogenesis. NSPC proliferation, viability and differentiation were assessed via neurosphere assay from neonatal mice. NSPC were incubated for 2 or 7 days with CBDV and Capsaicin (TRPV1 agonist) according to the experimental protocol. Three groups were tested: 1) control (no drugs); 2) CBDV (100nM; 300nM; 1M); 3) Capsaicin (3M; 10M; 30M). We observed that CBDV promoted a significant increase in the number of proliferative cells, while capsaicin had only an effect at the lowest concentration. Moreover, CBDV was shown to protect cells from cell death while capsaicin decreased cell viability. Concerning oligodendroglial differentiation, Capsaicin promoted a decrease in the number of oligodendrocyte progenitor cells (OPC) when compared with the control condition, while OPC maturation into myelinating oligodendrocytes was impaired by CBDV and Capsaicin. Interestingly, both drugs seem to promote neuronal differentiation. These results show that while both TRPV1 agonists are able to promote neuronal differentiation in SVZ cultures, CBDV is also able to induce neural stem cell proliferation and promote cell viability. Taken together, this non-psychotomimetic cannabinoid is an interesting therapeutic approach for stem cell therapies for future brain repair strategies.