Bitner Robert S, Bunnelle William H, Anderson David J, Briggs Clark A, Buccafusco Jerry, Curzon Peter, Decker Michael W, Frost Jennifer M, Gronlien Jens Halvard, Gubbins Earl, Li Jinhe, Malysz John, Markosyan Stella, Marsh Kennan, Meyer Michael D, Nikkel Arthur L, Radek Richard J, Robb Holly M, Timmermann Daniel, Sullivan James P, Gopalakrishnan Murali
Neuroscience Research, Global Pharmaceutical Research and Development, Abbott Laboratories, Abbott Park, Illinois 60064, USA.
J Neurosci. 2007 Sep 26;27(39):10578-87. doi: 10.1523/JNEUROSCI.2444-07.2007.
The alpha7 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 alpha7 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 (Ki = 10.8 nM) and human (Ki = 16.7 nM) alpha7 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 alpha7 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 alpha7 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 alpha7 binding affinities and behavioral efficacious doses. The MEK inhibitor SL327 completely blocked alpha7 agonist-evoked ERK1/2 phosphorylation. Our results demonstrate that alpha7 nAChR agonism 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.
α7烟碱型乙酰胆碱受体（nAChR）在认知过程中发挥着重要作用，可能是治疗神经退行性疾病和精神疾病认知缺陷的药物靶点。在本研究中，我们使用了一种新型的α7 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）来研究认知功效，并探讨认知的潜在细胞机制。A-582941对天然大鼠（Ki = 10.8 nM）和人类（Ki = 16.7 nM）α7 nAChRs具有高亲和力，在行为试验中增强了认知表现，这些试验包括猴子延迟匹配样本、大鼠社会识别和小鼠抑制性回避模型，分别捕捉工作记忆、短期识别记忆和长期记忆巩固的领域。此外，A-582941使大鼠以及表现出自然感觉门控缺陷的DBA/2小鼠中由α7 nAChR拮抗剂甲基lycaconitine诱导的感觉门控缺陷恢复正常。对已知参与认知功能的信号通路的研究表明，α7 nAChR激动作用增加了PC12细胞中细胞外信号调节激酶1/2（ERK1/2）的磷酸化。此外，在急性给予A-582941后，小鼠扣带回皮质和/或海马体中观察到ERK1/2和环磷酸腺苷反应元件结合蛋白（CREB）磷酸化增加，产生的血浆浓度在α7结合亲和力和行为有效剂量范围内。MEK抑制剂SL327完全阻断了α7激动剂诱发的ERK1/2磷酸化。我们的结果表明，α7 nAChR激动作用在增强ERK1/2和CREB磷酸化/激活的剂量下可在动物模型中产生广谱功效，可能代表一种有潜力改善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）相关的认知缺陷的机制。
