Unravelling a novel role for cannabidivarin in the modulation of subventricular zone postnatal neurogenesis

Diogo M. Lourenço, Rita Soares, Sónia Sá-Santos, Joana M. Mateus, Rui S. Rodrigues, João B. Moreira, Sandra H. Vaz, Ana M. Sebastião, Susana Solá, Sara Xapelli
European Journal of Pharmacology. 2023-11-01; 959: 176079
DOI: 10.1016/j.ejphar.2023.176079

1. Eur J Pharmacol. 2023 Nov 15;959:176079. doi: 10.1016/j.ejphar.2023.176079.
Epub 2023 Oct 5.

Unravelling a novel role for cannabidivarin in the modulation of subventricular
zone postnatal neurogenesis.

Lourenço DM(1), Soares R(2), Sá-Santos S(3), Mateus JM(1), Rodrigues RS(1),
Moreira JB(1), Vaz SH(1), Sebastião AM(1), Solá S(3), Xapelli S(4).

Author information:
(1)Instituto de Farmacologia e Neurociências, Faculdade de Medicina,
Universidade de Lisboa, 1649-028 Lisboa, Portugal; Instituto de Medicina
Molecular João Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa,
1649-028 Lisboa, Portugal.
(2)Instituto de Farmacologia e Neurociências, Faculdade de Medicina,
Universidade de Lisboa, 1649-028 Lisboa, Portugal; Instituto de Medicina
Molecular João Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa,
1649-028 Lisboa, Portugal; Instituto de Biologia Molecular, Faculdade de
Medicina, Universidade de Lisboa, 1649-028 Lisboa, Portugal.
(3)Research Institute for Medicines (iMed.ULisboa), Faculdade de Farmácia,
Universidade de Lisboa, 1649-003 Lisboa, Portugal.
(4)Instituto de Farmacologia e Neurociências, Faculdade de Medicina,
Universidade de Lisboa, 1649-028 Lisboa, Portugal; Instituto de Medicina
Molecular João Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa,
1649-028 Lisboa, Portugal. Electronic address: .

Postnatal neurogenesis has been shown to rely on the endocannabinoid system.
Here we aimed at unravelling the role of Cannabidivarin (CBDV), a
non-psychoactive cannabinoid, with high affinity for the non-classical
cannabinoid receptor TRPV1, on subventricular zone (SVZ) postnatal neurogenesis.
Using the neurosphere assay, SVZ-derived neural stem/progenitor cells (NSPCs)
were incubated with CBDV and/or 5′-Iodoresinferotoxin (TRPV1 antagonist), and
their role on cell viability, proliferation, and differentiation were dissected.
CBDV was able to promote, through a TRPV1-dependent mechanism, cell survival,
cell proliferation and neuronal differentiation. Furthermore, pulse-chase
experiments revealed that CBDV-induced neuronal differentiation was a result of
cell cycle exit of NSPCs. Regarding oligodendrocyte differentiation, CBDV
inhibited oligodendrocyte differentiation and maturation. Since our data
suggested that the CBDV-induced modulation of NSPCs acted via TRPV1, a
sodium-calcium channel, and that intracellular calcium levels are known
regulators of NSPCs fate and neuronal maturation, single cell calcium imaging
was performed to evaluate the functional response of SVZ-derived cells. We
observed that CBDV-responsive cells displayed a two-phase calcium influx
profile, being the initial phase dependent on TRPV1 activation. Taken together,
this work unveiled a novel and untapped neurogenic potential of CBDV via TRPV1
modulation. These findings pave the way to future neural stem cell biological
studies and repair strategies by repurposing this non-psychoactive cannabinoid
as a valuable therapeutic target.