Abdipranoto Andrea, Wu Sara, Stayte Sandy, Vissel Bryce
Neural Plasticity and Regeneration Group, Neuroscience Program, Garvan Institute of Medical Research, Darlinghurst, NSW, Australia.
CNS Neurol Disord Drug Targets. 2008 Apr;7(2):187-210. doi: 10.2174/187152708784083858.
Neurodegenerative diseases are characterised by a net loss of neurons from specific regions of the central nervous system (CNS). Until recently, research has focused on identifying mechanisms that lead to neurodegeneration, while therapeutic approaches have been primarily targeted to prevent neuronal loss. This has had limited success and marketed pharmaceuticals do not have dramatic benefits. Here we suggest that the future success of therapeutic strategies will depend on consideration and understanding of the role of neurogenesis in the adult CNS. We summarize evidence suggesting that neurogenesis is impaired in neurodegenerative diseases such as Parkinson's, Alzheimer's and Amyotrophic Lateral Sclerosis, while it is enhanced in stroke. We review studies where stimulation of neurogenesis is associated with restored function in animal models of these diseases, suggesting that neurogenesis is functionally important. We show that many current therapeutics, developed to block degeneration or to provide symptomatic relief, serendipitously stimulate neurogenesis or, at least, do not interfere with it. Importantly, many receptors, ion channels and ligand-gated channels implicated in neurodegeneration, such as NMDA, AMPA, GABA and nicotinic acetylcholine receptors, also play an important role in neurogenesis and regeneration. Therefore, new therapeutics targeted to block degeneration by antagonizing these channels may have limited benefit as they may also block regeneration. Our conclusion is that future drug development must consider neurogenesis. It appears unlikely that drugs being developed to treat neurodegenerative diseases will be beneficial if they impair neurogenesis. And, most tantalizing, therapeutic approaches that stimulate neurogenesis might stimulate repair and even recovery from these devastating diseases.
神经退行性疾病的特征是中枢神经系统（CNS）特定区域的神经元出现净损失。直到最近，研究一直集中在确定导致神经退行性变的机制上，而治疗方法主要旨在预防神经元损失。这取得的成功有限，市面上的药物并没有显著疗效。在此，我们认为治疗策略未来的成功将取决于对成体中枢神经系统中神经发生作用的考量和理解。我们总结了相关证据，这些证据表明在帕金森病、阿尔茨海默病和肌萎缩侧索硬化等神经退行性疾病中神经发生受损，而在中风中神经发生增强。我们回顾了一些研究，在这些疾病的动物模型中，神经发生的刺激与功能恢复相关，这表明神经发生在功能上很重要。我们表明，许多目前为阻止退变或提供症状缓解而开发的疗法，意外地刺激了神经发生，或者至少没有干扰神经发生。重要的是，许多与神经退行性变有关的受体、离子通道和配体门控通道，如N-甲基-D-天冬氨酸（NMDA）、α-氨基-3-羟基-5-甲基-4-异恶唑丙酸（AMPA）、γ-氨基丁酸（GABA）和烟碱型乙酰胆碱受体，在神经发生和再生中也起着重要作用。因此，通过拮抗这些通道来阻止退变的新疗法可能益处有限，因为它们也可能阻断再生。我们的结论是，未来的药物开发必须考虑神经发生。如果正在开发的治疗神经退行性疾病的药物损害神经发生，那么它们似乎不太可能有益。而且，最诱人的是，刺激神经发生的治疗方法可能会刺激修复，甚至从这些毁灭性疾病中恢复。
