ABSTRACT
Title
Alpha2-delta ligands as novel positive modulators of adult mouse neurogenesis in vitro and in vivo.
Authors
V. Bortolotto1,2, M.M. Valente1,2, V. Meneghini1,2, PL. Canonico2, M. Grilli1,2.
1Laboratory of Neuroplasticity and Pain, 2DISCAFF-DFB Center, University of Piemonte Orientale “A. Avogadro”, Novara, Italy.
1Laboratory of Neuroplasticity and Pain, 2DISCAFF-DFB Center, University of Piemonte Orientale “A. Avogadro”, Novara, Italy.
Abstract
The formation of new neurons, starting from neural progenitors cells (NPC), still occurs in the adult mammalian brain. The functional role of this process, referred to as adult neurogenesis, is still unclear, but several studies suggest that it is deregulated in various neuropsychiatric disorders (Kempermann et al., 2008). Additionally, literature data suggest that some psychoactive drugs (antidepressants, mood stabilizers, antipsychotics) can positively affect adult neurogenesis (DeCarolis et al., 2010) leading to the exciting possibility of its pharmacological modulation as a therapeutic strategy in CNS diseases. We studied the potential effect of clinically relevant anticonvulsants such as carbamazepine, oxacarbazepine, gabapentin (GBP), pregabalin (PGB), mephenytoin and ethosuximide on the in vitro differentiation of adult mouse hippocampal neural progenitors cells (NPC) towards the neuronal lineage. Among tested drugs only the alpha-2-delta (α2-δ) ligands PGB and GBP increased, in a concentration-dependent manner, the number of newborn mature and immature neurons generated from adult NPC, and in parallel decreased the number of undifferentiated/progenitor cells. Moreover PGB effects on adult hippocampal neurogenesis were also demonstrated in vivo after chronic administration (1 mpk and 10 mpk, i.p.) in adult CD1 male mice. We observed that 10 mpk PGB significantly decreased the percentage of BrdU single positive cells and increased the percentage of newly generated hippocampal neurons (Brdu+/NeuN+ cells), with no effect on Brdu+/GFAP+ cells. Furthermore, the total number of BrdU+ cells was not different in PGB- vs vehicle-treated animals, suggesting that PGB did not affect new hippocampal cell survival.
Since PGB and GPB concentrations which were active in vitro on neuronal differentiation of adult NPC closely correlated with their binding affinities for the α2-δ subunit of neuronal voltage-gated calcium channels, we also tested the effect of the α2-δ antagonist L-isoleucine on the pro-neurogenic activity of these drugs. L-isoleucine (1-300 nM) counteracted the pro-neurogenic effect of PGB and GBP in a concentration-dependent manner.
Finally, we demonstrated that activation of the NF-κB signaling pathway is involved in PGB- and GBP-mediated effects on adult NPC differentiation towards the neuronal lineage.
In conclusion, we demonstrated that the α2-δ ligands PGB and GBP, clinically relevant drugs utilized as anticonvulsants, analgesics and anxiolytics, have a novel pharmacological property, namely the modulation of adult neurogenesis both in vitro and in vivo.
Kempermann et al. (2008). Curr Opin Psychiatry 21: 290-295.
DeCarolis, Eisch (2010). Neuropharmacology 58(6): 884-893.
Since PGB and GPB concentrations which were active in vitro on neuronal differentiation of adult NPC closely correlated with their binding affinities for the α2-δ subunit of neuronal voltage-gated calcium channels, we also tested the effect of the α2-δ antagonist L-isoleucine on the pro-neurogenic activity of these drugs. L-isoleucine (1-300 nM) counteracted the pro-neurogenic effect of PGB and GBP in a concentration-dependent manner.
Finally, we demonstrated that activation of the NF-κB signaling pathway is involved in PGB- and GBP-mediated effects on adult NPC differentiation towards the neuronal lineage.
In conclusion, we demonstrated that the α2-δ ligands PGB and GBP, clinically relevant drugs utilized as anticonvulsants, analgesics and anxiolytics, have a novel pharmacological property, namely the modulation of adult neurogenesis both in vitro and in vivo.
Kempermann et al. (2008). Curr Opin Psychiatry 21: 290-295.
DeCarolis, Eisch (2010). Neuropharmacology 58(6): 884-893.