Peterson Amie L, Nutt John G
Parkinsons Disease Research, Educational and Clinical Center, Portland Veteran's Administration Medical Center, Portland, Oregon 97239, USA.
Neurotherapeutics. 2008 Apr;5(2):270-80. doi: 10.1016/j.nurt.2008.02.003.
Trophic factors are proteins that support and protect subpopulations of cells. A number have been reported to act on dopaminergic neurons in vitro and in vivo, making them potential therapeutic candidates for Parkinson's disease. All of these candidate factors protect dopaminergic neurons if given prior to, or with, selective neurotoxins. Fewer trophic factors, primarily glial-derived neurotrophic factor (GDNF) and its relative, neurturin (NRTN; also known as NTN), have been shown to restore function in damaged dopamine neurons after the acute effects of neurotoxins have subsided. A major barrier to clinical translation has been delivery. GDNF delivered by intracerebroventricular injection in patients was ineffective, probably because GDNF did not reach the target, the putamen, and intraputaminal infusion was ineffective, probably because of limited distribution within the putamen. A randomized clinical trial with gene therapy for NRTN is underway, in an attempt to overcome these problems with targeting and distribution. Other strategies are available to induce trophic effects in the CNS, but have not yet been the focus of human research. To date, clinical trials have focused on restoration of function (i.e., improvement of parkinsonism). Protection (i.e., slowing or halting disease progression and functional decline) might be a more robust effect of trophic agents. Laboratory research points to their effectiveness in protecting neurons and even restoring dopaminergic function after a monophasic neurotoxic insult. Utility for such compounds in patients with Parkinson's disease and ongoing loss of dopaminergic neurons remains to be proven.
营养因子是支持和保护细胞亚群的蛋白质。据报道，有几种营养因子在体外和体内对多巴胺能神经元起作用，使其成为帕金森病潜在的治疗候选物。如果在给予选择性神经毒素之前或同时给予所有这些候选因子，它们都能保护多巴胺能神经元。较少的营养因子，主要是胶质细胞源性神经营养因子（GDNF）及其相关物神经营养素（NRTN；也称为NTN），已被证明在神经毒素的急性作用消退后能恢复受损多巴胺神经元的功能。临床转化的一个主要障碍是递送。在患者中通过脑室内注射递送的GDNF无效，可能是因为GDNF未到达靶点壳核，而壳核内输注也无效，可能是因为在壳核内的分布有限。一项关于NRTN基因治疗的随机临床试验正在进行，试图克服靶向和分布方面的这些问题。还有其他策略可用于在中枢神经系统中诱导营养作用，但尚未成为人类研究的重点。迄今为止，临床试验主要集中在功能恢复（即改善帕金森症状）。保护作用（即减缓或阻止疾病进展和功能衰退）可能是营养剂更显著的效果。实验室研究表明它们在保护神经元甚至在单相神经毒性损伤后恢复多巴胺能功能方面是有效的。这些化合物在帕金森病患者和多巴胺能神经元持续丧失的情况下的效用仍有待证实。
