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
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
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DOI：
10.1124/jpet.106.114108
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发表时间：
2007-02-01
影响因子：
3.5
通讯作者：
Yamada, Kiyofumi
中科院分区：
文献类型：
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作者：
Ito, Yukio;Takuma, Kazuhiro;Yamada, Kiyofumi
研究了ZSET1446（Spiro [Imidazo [1,2-A]吡啶-3,2-Indan] -2（3H）-ONE）对小鼠认知障碍的影响，以前在以前用甲基苯丙胺（METH）在1 mg/kg的剂量下治疗了7天。 ZSET1446表现出对甲基苯丙胺诱导的识别记忆障碍的显着改善作用，尽管它对探索行为没有影响。 ZSET1446（1 MU G/kg）回收了新颖性信号调节的激酶1/2（ERK1/2）在甲基甲状化小鼠的前额叶皮层（PFC）中的缺陷。化合物在海马中增加了磷酸化的ERK1/2水平，而不会影响天真小鼠的PFC，而不会影响总ERK1/2水平。 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).此外，多巴胺D1受体拮抗剂，SCH23390 [R - （+） - 7-氯-8-羟基-3-羟基-3-甲基-1-苯基-1-苯基-2,3,4,5- tetrahydro-1H-3-3-3-3-3-3-3-3-苯甲酰氨基]和N-甲基 - 甲基 - 甲基 - 甲基 - 甲基 - 甲基 - 甲基（N-NMDDA）的受体 - - - and-nmdda）。 [5H-Dibenzo [A，D]环旋t-5,10-Imine（Dizocilpine Maleate）]，阻止了ZSET1446对甲基甲基苯酚诱导的记忆障碍的改善作用，而D2受体拮抗剂Raclopride则没有作用。这些结果表明，在用PFC的多巴胺D1和NMDA受体刺激后，ZSET1446对甲基甲基记忆障碍的改善作用与ERK1/2的间接激活有关。 ZSET1446将是旨在治疗阿尔茨海默氏病和精神分裂症的认知缺陷以及METH精神病的潜在候选者。
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 mu g/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.