RT Journal Article
SR Electronic
T1 A Novel Azaindolizinone Derivative ZSET1446 (Spiro[imidazo[1,2-<em>a</em>]pyridine-3,2-indan]-2(3<em>H</em>)-one) Improves Methamphetamine-Induced Impairment of Recognition Memory in Mice by Activating Extracellular Signal-Regulated Kinase 1/2
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP 819
OP 827
DO 10.1124/jpet.106.114108
VO 320
IS 2
A1 Yukio Ito
A1 Kazuhiro Takuma
A1 Hiroyuki Mizoguchi
A1 Taku Nagai
A1 Kiyofumi Yamada
YR 2007
UL http://jpet.aspetjournals.org/content/320/2/819.abstract
AB The effect of ZSET1446 (spiro[imidazo[1,2-a]pyridine-3,2-indan]-2(3H)-one) on cognitive impairment in mice, previously treated with methamphetamine (METH) at a dose of 1 mg/kg for 7 days, was investigated. ZSET1446 showed a significant ameliorating effect on METH-induced impairment of recognition memory, although it had no effect on exploratory behavior. ZSET1446 (1 μg/kg) recovered the defect of the novelty-induced activation of extracellular signal-regulated kinase 1/2 (ERK1/2) in the prefrontal cortex (PFC) of METH-treated mice. The compound increased phosphorylated ERK1/2 levels in the hippocampus but not PFC of naive mice without affecting the total ERK1/2 levels. The ameliorating effect of ZSET1446 on recognition memory in METH-treated mice was negated by pretreatment with a mitogen-activated protein kinase/extracellular signal-regulated kinase kinase inhibitor, SL327 (α-[amino-(4-aminophenylthio)methylene]-2-(trifluoromethyl)phenylacetonitrile). Furthermore, the dopamine D1 receptor antagonist, SCH23390 [R-(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine], and N-methyl-d-aspartate (NMDA) receptor antagonist, MK-801 [5H-dibenzo[a,d]cyclohepten-5,10-imine (dizocilpine maleate)], blocked the ameliorating effect of ZSET1446 on METH-induced memory impairment, whereas the D2 receptor antagonist, raclopride, had no effect. These results suggest that the ameliorative effect of ZSET1446 on METH-induced memory impairment is associated with indirect activation of ERK1/2 following stimulation with dopamine D1 and NMDA receptors of the PFC. ZSET1446 would be a potential candidate for further preclinical study aimed at the treatment of cognitive deficits in Alzheimer's disease and schizophrenia, as well as METH psychosis. The American Society for Pharmacology and Experimental Therapeutics