CNRS, Univ. Bordeaux, INCIA UMR 5287, Bordeaux, France.
Neurobiol Aging. 2013 Jun;34(6):1599-609. doi: 10.1016/j.neurobiolaging.2012.10.006. Epub 2013 Jan 23.
The present study investigates in aged mice the working memory (WM) enhancing potential of the selective α4β2* nicotinic receptor agonist S 38232 as compared with the cholinesterase inhibitor donepezil, and their effect on cAMP response element binding protein (CREB) phosphorylation (pCREB) as a marker of neuronal activity. We first showed that aged mice exhibit a WM deficit and an increase of pCREB in the prelimbic cortex (PL) as compared with young mice, whereas no modification appears in the CA1. Further, we showed that systemic administration of S 38232 restored WM in aged mice and alleviated PL CREB overphosphorylation. Donepezil alleviated age-related memory deficits, however, by increasing pCREB in the CA1, while pCREB in PL remained unaffected. Finally, whereas neuronal inhibition by lidocaine infusion in the PL appeared deleterious in young mice, the infusion of Rp-cAMPS (a compound known to inhibit CREB phosphorylation) or S 38232 rescued WM in aged animals. Thus, by targeting the α4β2*-nicotinic receptor of the PL, S 38232 alleviates PL CREB overphosphorylation and restores WM in aged mice, which opens new pharmacologic perspectives of therapeutic strategy.
本研究在老年小鼠中考察了选择性α4β2烟碱受体激动剂 S 38232 与胆碱酯酶抑制剂多奈哌齐相比增强工作记忆（WM）的潜力，以及它们对 cAMP 反应元件结合蛋白（CREB）磷酸化（pCREB）的影响，作为神经元活动的标志物。我们首先表明，与年轻小鼠相比，老年小鼠表现出 WM 缺陷和前额皮质（PL）中 pCREB 的增加，而 CA1 中没有变化。此外，我们表明，全身给予 S 38232 可恢复老年小鼠的 WM，并减轻 PL CREB 的过度磷酸化。多奈哌齐通过增加 CA1 中的 pCREB 缓解了与年龄相关的记忆缺陷，而 PL 中的 pCREB 则不受影响。最后，尽管利多卡因在 PL 中的神经元抑制在年轻小鼠中表现出有害作用，但 Rp-cAMPS（一种已知抑制 CREB 磷酸化的化合物）或 S 38232 的输注挽救了老年动物的 WM。因此，通过靶向 PL 的α4β2-烟碱受体，S 38232 减轻了 PL CREB 的过度磷酸化并恢复了老年小鼠的 WM，为治疗策略开辟了新的药理学前景。
