PT  - JOURNAL ARTICLE
AU  - Maria Maddalena Valente
AU  - Valeria Bortolotto
AU  - Bruna Cuccurazzu
AU  - Federica Ubezio
AU  - Vasco Meneghini
AU  - Maria Teresa Francese
AU  - Pier Luigi Canonico
AU  - Mariagrazia Grilli
TI  - α2δ Ligands Act as Positive Modulators of Adult Hippocampal Neurogenesis and Prevent Depressive-like Behavior Induced by Chronic Restraint Stress.
AID  - 10.1124/mol.112.077636
DP  - 2012 Jan 01
TA  - Molecular Pharmacology
PG  - mol.112.077636
4099  - http://molpharm.aspetjournals.org/content/early/2012/05/09/mol.112.077636.short
4100  - http://molpharm.aspetjournals.org/content/early/2012/05/09/mol.112.077636.full
AB  - Although the role of adult hippocampal neurogenesis remains to be fully elucidated, several studies suggest that the process is involved in cognitive and emotional functions and deregulated in various neuropsychiatric disorders, including major depression. Interestingly, several psychoactive drugs, including antidepressants, can modulate adult neurogenesis. Here we show for the first time that the alpha2delta α2δ ligands gabapentin [1-(aminomethyl)cyclohexaneacetic acid; GBP] and pregabalin [S-[+]-3-isobutylGABA or (S)-3-(aminomethyl)-5-methylhexanoic acid; PGB] can produce a concentration-dependent increase in the number of newborn mature and immature neurons generated in vitro from adult hippocampal neural progenitor cells (NPC), and, in parallel, a decrease in the number of undifferentiated precursor cells. These effects were confirmed in vivo, since a significantly increased number of adult generated neurons was observed in the hippocampal region of mice chronically treated with PGB [10 mg/kg, i.p., 21 days] compared to vehicle-treated mice. Moreover, we demonstrated that PGB administration prevented the appearance of depression-like behaviours induced by chronic restraint stress and, in parallel, promoted hippocampal neurogenesis in adult stressed mice. Finally, we provided data suggesting the potential involvement of the α2δ subunit and NF-κB signaling pathway in the drug-mediated proneurogenic effects. The new pharmacological activities of α2δ ligands may help explaining their therapeutic activity as add-on therapy in major depression and on depressive symptoms in posttraumatic stress disorder and generalized anxiety disorders. Furthermore these data contribute to the identification of novel molecular pathways which may represent potential targets for pharmacological modulation in depression.