Abstract |
Olfactory bulbectomy (OBX) in mice elicits impaired memory and cognitive functions. Here, we found that chronic oral administration of spiro[imidazo[1,2-a] pyridine-3,2- indan]-2(3H)-one ( ZSET1446/ST101) (0.1-1 mg/kg/day), a novel cognitive enhancer, significantly improved memory deficits as assessed by Y-maze and novel object recognition tasks in OBX mice. Immunostaining of cholinergic neurons in the medial septum by using an anti- choline acetyltransferase antibody indicated that chronic ZSET1446 treatment did not rescue cholinergic neurons. However, chronic treatment significantly restored OBX-induced decreases both in calcium/calmodulin-dependent protein kinase II ( CaMKII) and protein kinase C (PKC) phosphorylation without improving decreased extracellular signal-regulated kinase phosphorylation in the hippocampal CA1 region. Consistent with enhanced CaMKII and PKC phosphorylation, ZSET1446 treatment improved glutamate receptor 1 (Ser-831) phosphorylation in the hippocampal CA1 region. ZSET1446 treatment also significantly rescued impaired long-term potentiation (LTP) in the hippocampal CA1 region of OBX mice. Taken together, the cognition-enhancing effect of ZSET1446 is probably mediated in part by stimulation of CaMKII and PKC activities, which in turn rescue impaired hippocampal LTP in OBX mice.
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Authors | Feng Han, Norifumi Shioda, Shigeki Moriguchi, Yui Yamamoto, Alisa Y Ali Raie, Yoshimasa Yamaguchi, Masataka Hino, Kohji Fukunaga |
Journal | The Journal of pharmacology and experimental therapeutics
(J Pharmacol Exp Ther)
Vol. 326
Issue 1
Pg. 127-34
(Jul 2008)
ISSN: 1521-0103 [Electronic] United States |
PMID | 18388258
(Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)
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Chemical References |
- Indans
- Spiro Compounds
- spiro(imidazo-(1,2-a)pyridine-3,2-indan)-2(3H)-one
- Protein Kinase C
- Calcium-Calmodulin-Dependent Protein Kinase Type 2
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Topics |
- Animals
- Calcium-Calmodulin-Dependent Protein Kinase Type 2
(metabolism)
- Enzyme Activation
(drug effects, physiology)
- Hippocampus
(drug effects, enzymology)
- Indans
(pharmacology, therapeutic use)
- Male
- Memory Disorders
(drug therapy, enzymology)
- Mice
- Olfactory Bulb
(enzymology, surgery)
- Protein Kinase C
(metabolism)
- Spiro Compounds
(pharmacology, therapeutic use)
- Treatment Outcome
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