Tuszynski Mark H
Department of Neurosciences-0626, University of California-San Diego, La Jolla 92161, and Veterans Affairs Medical Center, San Diego, CA, USA.
Alzheimer Dis Assoc Disord. 2007 Apr-Jun;21(2):179-89. doi: 10.1097/WAD.0b013e318068d6d2.
Nervous system growth factors potently stimulate cell function and prevent neuronal death. These broad effects on survival and function arise from direct downstream activation of antiapoptotic pathways, inhibition of proapoptotic pathways, and stimulation of functionally important cellular mechanisms including ERK/MAP kinase and CREB. Thus, as a class, growth factors offer the potential to treat neurodegenerative disorders for the first time by preventing neuronal degeneration rather than compensating for cell loss after it has occurred. Different growth factors affect distinct and specific populations of neurons: the first nervous system growth factor identified, nerve growth factor, potentially stimulates the survival and function of basal forebrain cholinergic neurons, suggesting that nerve growth factor could be a means for reducing the cholinergic component of cell degeneration in Alzheimer disease. This review will discuss the transition of growth factors from preclinical studies to human clinical trials in Alzheimer disease. The implementation of clinical testing of growth factor therapy for neurologic disease has been constrained by the dual need to achieve adequate concentrations of these proteins in specific brain regions containing degenerating neurons, and preventing growth factor spread to nontargeted regions to avoid adverse effects. Gene therapy is one of a limited number of potential methods for achieving these requirements.
神经系统生长因子能有效刺激细胞功能并防止神经元死亡。这些对生存和功能的广泛影响源于抗凋亡途径的直接下游激活、促凋亡途径的抑制以及对包括ERK/MAP激酶和CREB在内的功能重要的细胞机制的刺激。因此，作为一类物质，生长因子首次提供了通过预防神经元变性而非在细胞损失发生后进行补偿来治疗神经退行性疾病的潜力。不同的生长因子影响不同且特定的神经元群体：最早被鉴定出的神经系统生长因子——神经生长因子，有可能刺激基底前脑胆碱能神经元的存活和功能，这表明神经生长因子可能是减少阿尔茨海默病中细胞变性胆碱能成分的一种手段。本综述将讨论生长因子从阿尔茨海默病的临床前研究到人体临床试验的转变。生长因子疗法用于神经系统疾病的临床试验实施受到双重需求的限制，即需要在含有退化神经元的特定脑区达到这些蛋白质的足够浓度，并防止生长因子扩散到非靶向区域以避免不良反应。基因治疗是实现这些要求的少数潜在方法之一。
