Broad-spectrum efficacy across cognitive domains by α7 nicotinic acetylcholine receptor agonism correlates with activation of ERK1/2 and CREB phosphorylation pathways
Broad-spectrum efficacy across cognitive domains by α7 nicotinic acetylcholine receptor agonism correlates with activation of ERK1/2 and CREB phosphorylation pathways
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DOI：
10.1523/jneurosci.2444-07.2007
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发表时间：
2007-09-26
影响因子：
5.3
通讯作者：
Gopalakrishnan, Murali
中科院分区：
文献类型：
--
作者：
Bitner, Robert S.;Bunnelle, William H.;Gopalakrishnan, Murali
α 7烟碱乙酰胆碱受体（nAChR）在认知过程中起重要作用，并且可以代表用于治疗神经退行性疾病和精神疾病中的认知缺陷的药物靶标。在本研究中，我们使用了一种新型的α 7 nAChR选择性激动剂，2-甲基-5-（6-苯基-哒嗪-3-基）-八氢-吡咯并[3，4-c]吡咯（A-582941）来询问认知功效，以及检查认知的潜在细胞机制。A-582941对天然大鼠（K（i）= 10.8 nM）和人（Ki = 16.7 nM）α 7 nAChR表现出高亲和力，可增强行为试验中的认知表现，包括猴延迟匹配样本、大鼠社会识别和小鼠抑制性回避模型，这些模型分别捕获工作记忆、短期识别记忆和长期记忆巩固的结构域。此外，A-582941使大鼠和DBA/2小鼠中由α 7 nAChR拮抗剂甲基乌头碱诱导的感觉门控缺陷正常化，这些小鼠表现出天然感觉门控缺陷。对已知参与认知功能的信号通路的检查显示，α 7 nAChR激动增加了PC12细胞中的细胞外信号调节激酶12（ERK 12）磷酸化。此外，急性A-582941给药后，在小鼠扣带回皮质和/或海马中观察到ERK 1/2和cAMP反应元件结合蛋白（CREB）磷酸化增加，产生的血浆浓度在α 7结合亲和力和行为有效剂量范围内。MEK抑制剂SL327完全阻断α 7激动剂诱发的ERK 1/2磷酸化。我们的研究结果表明，α 7nAChRagonism可以导致广谱的功效，在动物模型中的剂量，增强ERK 1/2和CREB磷酸化/激活，并可能代表一种机制，提供了改善认知缺陷与神经退行性疾病和精神疾病，如阿尔茨海默病和精神分裂症。
The alpha 7 nicotinic acetylcholine receptor (nAChR) plays an important role in cognitive processes and may represent a drug target for treating cognitive deficits in neurodegenerative and psychiatric disorders. In the present study, we used a novel alpha 7 nAChR-selective agonist, 2-methyl-5-(6-phenyl-pyridazin-3-yl)-octahydro-pyrrolo[ 3,4-c] pyrrole (A-582941) to interrogate cognitive efficacy, as well as examine potential cellular mechanisms of cognition. Exhibiting high affinity to native rat (K(i) = 10.8 nM) and human (Ki = 16.7 nM) alpha 7 nAChRs, A-582941 enhanced cognitive performance in behavioral assays including the monkey delayed matching-to-sample, rat social recognition, and mouse inhibitory avoidance models that capture domains of working memory, short-term recognition memory, and long-term memory consolidation, respectively. In addition, A-582941 normalized sensory gating deficits induced by the alpha 7 nAChR antagonist methyllycaconitine in rats, and in DBA/2 mice that exhibit a natural sensory gating deficit. Examination of signaling pathways known to be involved in cognitive function revealed that alpha 7 nAChR agonism increased extracellular-signal regulated kinase 1/2 (ERK1/2) phosphorylation in PC12 cells. Furthermore, increases in ERK1/2 and cAMP response element-binding protein (CREB) phosphorylation were observed in mouse cingulate cortex and/or hippocampus after acute A-582941 administration producing plasma concentrations in the range of alpha 7 binding affinities and behavioral efficacious doses. The MEK inhibitor SL327 completely blocked alpha 7 agonist-evoked ERK1/2 phosphorylation. Our results demonstrate that alpha 7nAChRagonism can lead to broad-spectrum efficacy in animal models at doses that enhance ERK1/2 and CREB phosphorylation/activation and may represent a mechanism that offers potential to improve cognitive deficits associated with neurodegenerative and psychiatric diseases, such as Alzheimer's disease and schizophrenia.