A novel cognitive enhancer, ZSET1446/ST101, promotes hippocampal neurogenesis and ameliorates depressive behavior in olfactory bulbectomized mice

• Published in: The Journal of pharmacology and experimental therapeutics 2010-04, Vol.333 (1), p.43-50
• Main Authors: Shioda, Norifumi, Yamamoto, Yui, Han, Feng, Moriguchi, Shigeki, Yamaguchi, Yoshimasa, Hino, Masataka, Fukunaga, Kohji
• Format: Article
• Language: English
• Subjects: Animals; Behavior, Animal - drug effects; Dentate Gyrus - drug effects; Dentate Gyrus - pathology; Depression - drug therapy; Depression - etiology; Dose-Response Relationship, Drug; Extracellular Signal-Regulated MAP Kinases - physiology; Hippocampus - drug effects; Hippocampus - pathology; Indans - pharmacology; Indans - therapeutic use; Male; Mecamylamine - pharmacology; Mice; Neurogenesis; Neurons - drug effects; Neurons - pathology; Nicotinic Antagonists - pharmacology; Nootropic Agents - pharmacology; Nootropic Agents - therapeutic use; Olfactory Bulb; Phosphatidylinositol 3-Kinases - physiology; Proto-Oncogene Proteins c-akt - physiology; Receptors, Nicotinic - physiology; Signal Transduction; Spiro Compounds - pharmacology; Spiro Compounds - therapeutic use
• ISSN: 0022-3565; 1521-0103
• DOI: 10.1124/jpet.109.163535

In the adult brain, neurogenesis persistently occurs in the subgranular zone of the hippocampal dentate gyrus (DG), and impaired neurogenesis is implicated in depressive behaviors and poor learning memory. Here, we investigated the effects of oral administration of spiro[imidazo[1,2-a]pyridine-3,2-indan]-2(3H)-one (ZSET1446/ST101), a novel cognitive enhancer stimulating acetylcholine release, on adult neurogenesis in olfactory bulbectomized (OBX) mice. OBX mice showed significant decreases in the number of newborn cells in the DG by immunohistochemical analysis of 5-bromo-2-deoxyuridine incorporation. Impaired neurogenesis observed in OBX mice was significantly improved by chronic administration with ZSET1446. We confirmed that administration with mecamylamine, a nicotinic acetylcholine receptor antagonist, inhibits ZSET1446-enhanced neurogenesis in the DG. ZSET1446 administration also restored decreased phosphorylation of Akt and extracellular signal-regulated kinase in the DG of OBX mice. Consistent with restored neurogenesis, chronic but not single ZSET1446 administration promoted significant decreases in immobility in tail suspension tests and improved cognitive behaviors in OBX mice. Taken together, chronic ZSET1446 administration antagonized impaired neurogenesis seen in OBX mice, an effect closely associated with improvement of depressive behavior.