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A novel azaindolizinone derivative ZSET1446 (spiro[imidazo[1,2-a]pyridine-3,2-indan]-2(3H)-one) improves methamphetamine-induced impairment of recognition memory in mice by activating extracellular signal-regulated kinase 1/2.

Abstract
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 microg/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 (alpha-[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.
AuthorsYukio Ito, Kazuhiro Takuma, Hiroyuki Mizoguchi, Taku Nagai, Kiyofumi Yamada
JournalThe Journal of pharmacology and experimental therapeutics (J Pharmacol Exp Ther) Vol. 320 Issue 2 Pg. 819-27 (Feb 2007) ISSN: 0022-3565 [Print] United States
PMID17090702 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Benzazepines
  • Indans
  • Spiro Compounds
  • spiro(imidazo-(1,2-a)pyridine-3,2-indan)-2(3H)-one
  • Methamphetamine
  • Dizocilpine Maleate
  • Mitogen-Activated Protein Kinase 1
  • Mitogen-Activated Protein Kinase 3
Topics
  • Animals
  • Benzazepines (pharmacology)
  • Cognition (drug effects)
  • Dizocilpine Maleate (pharmacology)
  • Enzyme Activation
  • Indans (pharmacology)
  • Long-Term Potentiation (drug effects)
  • Male
  • Methamphetamine (toxicity)
  • Mice
  • Mice, Inbred ICR
  • Mitogen-Activated Protein Kinase 1 (metabolism)
  • Mitogen-Activated Protein Kinase 3 (metabolism)
  • Prefrontal Cortex (enzymology)
  • Spiro Compounds (pharmacology)

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