Synaptic Plasticity and Neural Network Dynamics Discovery Performance Unit, Neurosciences CEDD, GlaxoSmithKline, New Frontiers Science Park, Harlow, Essex, CM19 5AW, UK.
Neuropharmacology. 2010 Nov;59(6):437-43. doi: 10.1016/j.neuropharm.2010.06.005. Epub 2010 Jun 23.
One of the major neuropathological hallmarks in Alzheimer's disease (AD) is the loss of cholinergic neurones of the nucleus basalis of Meynert (NbM). This consistent finding gave rise to the 'cholinergic' hypothesis of AD and lead to the subsequent development of acetylcholinesterase (AChE) inhibitors; the first class of drug to be approved for the treatment of AD. However, several studies have questioned the efficacy of using AChE inhibitors in AD. In this study we have investigated the ability of two AChE inhibitors, donepezil (Aricept) and physostigmine, to induce gamma oscillatory activity in rat hippocampal slices; network activity believed to play a role in higher cognitive function. We report here that donepezil is capable of inducing gamma oscillations in region CA3 of rat hippocampal slices, which may contribute to its procognitive action. However, donepezil-induced gamma oscillations are weak in comparison to physostigmine. We also explore the activity of novel agents with known procognitive activity, and show that one such agent, the M(1) muscarinic acetylcholine receptor agonist, 77-LH-28-1, can significantly enhance donepezil-induced gamma oscillations. These data support the notion that it should be possible to find a more efficacious AChE inhibitor or an adjunctive approach, to provide a better therapeutic intervention in AD.
阿尔茨海默病（AD）的主要神经病理学特征之一是基底核梅内尔特胆碱能神经元的丧失。这一一致的发现催生了 AD 的“胆碱能”假说，并导致了乙酰胆碱酯酶（AChE）抑制剂的后续开发；这是第一类被批准用于治疗 AD 的药物。然而，多项研究对使用 AChE 抑制剂治疗 AD 的疗效提出了质疑。在这项研究中，我们研究了两种 AChE 抑制剂，多奈哌齐（Aricept）和毒扁豆碱，在诱导大鼠海马切片中γ振荡活动方面的能力；这种网络活动被认为在更高的认知功能中发挥作用。我们在这里报告，多奈哌齐能够在大鼠海马切片的 CA3 区诱导γ振荡，这可能有助于其认知前作用。然而，与毒扁豆碱相比，多奈哌齐诱导的γ振荡较弱。我们还探索了具有已知认知前活性的新型药物的活性，并表明此类药物之一，即 M1 毒蕈碱乙酰胆碱受体激动剂 77-LH-28-1，可显著增强多奈哌齐诱导的γ振荡。这些数据支持这样一种观点，即应该有可能找到更有效的 AChE 抑制剂或辅助方法，为 AD 提供更好的治疗干预。
