TNF-α inhibition as a treatment strategy for neurodegenerative disorders:: New drug candidates and targets
TNF-α inhibition as a treatment strategy for neurodegenerative disorders:: New drug candidates and targets
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DOI：
10.2174/156720507781788873
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发表时间：
2007-09-01
影响因子：
2.1
通讯作者：
Greig, Nigel H.
中科院分区：
文献类型：
--
作者：
Tweedie, David;Sambamurti, Kumar;Greig, Nigel H.
随着北美和欧洲人的平均年龄继续上升，与“老年”相关的疾病的发生率也同样增加。在这些疾病中，最明显的是与痴呆症相关的神经退行性疾病，如阿尔茨海默病(AD)、帕金森病(PD)和中风。虽然在早期阶段，这些情况与明显不同脑区的细胞功能障碍有关，因此影响不同类型的神经细胞；最有可能的是，最后阶段具有相似的细胞和分子过程，导致神经元死亡，并最终出现明显的临床症状。在这方面，从头部创伤到蛋白质突变和毒物暴露等不同的环境和遗传触发因素可能会引发一连串的细胞内事件，最终导致神经元死亡。一种强有力的候选触发蛋白，因此是治疗操作的潜在靶点是强大的促炎/促凋亡细胞因子，肿瘤坏死因子-α(TNF-α)。肿瘤坏死因子-α是由大脑驻留细胞(小胶质细胞)对各种刺激作出反应而分泌的。已证实它在AD、PD和肌萎缩侧索硬化症(ALS)以及其他几种中枢神经系统并发症的中枢神经系统(CNS)神经炎症介导的细胞死亡中发挥重要作用。最近，调节循环外周血中TNF-α蛋白水平的药物已被证明是有价值的治疗药物。Enbrel(依那西普)和Remicade(Infliximab)，这两种药物都显示出对抗类风湿性关节炎和其他外周炎症性疾病的有益特性。不幸的是，这些药物在很大程度上无法穿透血脑屏障，这严重限制了它们在中枢神经系统炎症环境中的使用。然而，沙利度胺是一种小分子药物，可以抑制肿瘤坏死因子-α蛋白的合成，而且与大分子不同，它很容易通过血脑屏障。因此，沙利度胺及其类似物是用于确定抗肿瘤坏死因子-α疗法在神经系统内炎症支持的各种疾病中的潜在价值的极佳候选药物。因此，我们选择讨论不受调控的肿瘤坏死因子-a在中枢神经系统疾病中的表达相关性，并在一定程度上与周围神经系统的疾病有关。此外，我们考虑使用沙利度胺衍生剂作为抗肿瘤坏死因子-α治疗药物在神经炎症环境中的应用。
As the average ages of North Americans and Europeans continue to rise; similarly the incidence of "old age" associated illnesses likewise increases. Most notably among these ailments are conditions linked to dementia-related neurodegenerative disorders, such as Alzheimer's disease (AD), Parkinson's disease (PD) and stroke. While in the early stages, these conditions are associated with cellular dysfunction in distinctly different brain regions, thus affecting different neuronal cell types; it is most likely that the final stages share similar cellular and molecular processes leading to neuronal death and ultimately overt clinical symptoms. In this regard, different environmental and genetic triggers ranging from head trauma to protein mutations and toxicological exposure may instigate a cascade of intracellular events that ultimately lead to neuronal death. One strong candidate trigger protein, and thus a potential target for therapeutic manipulation is the potent pro-inflammatory / pro-apoptotic cytokine, tumor necrosis factor-alpha (TNF-alpha). TNF-alpha is secreted by the brain resident marcophage (the microglial cell) in response to various stimuli. It has been demonstrated to play a major role in central nervous system (CNS) neuroinflammation-mediated cell death in AD, PD and amyotrophic lateral sclerosis (ALS) as well as several other CNS complications.Recently, agents that modulate the levels of circulating peripheral TNF-alpha protein have been shown to be worthwhile therapeutic agents with the use. of Enbrel (Etanercept) and Remicade (Infliximab), both of which display beneficial properties against rheumatoid arthritis and other peripheral inflammatory diseases. Unfortunately, these agents are largely unable to penetrate the blood-brain barrier, which severely limits their use in the setting of neuroinflammation in the CNS. However, thalidomide, a small molecule drug, can inhibit TNF-alpha protein synthesis and, unlike larger molecules, is readily capable of crossing the blood-brain barrier. Thus thalidomide and its analogs are excellent candidate agents for use in determining the potential value of anti-TNF-alpha therapies in a variety of diseases underpinned by inflammation within the nervous system. Consequently, we have chosen to discuss the relevance of unregulated TNF-a expression in illnesses of the CNS and, to an extent, the peripheral nervous system. Additionally, we consider the utilization of thalidomide-derived agents as anti-TNF-alpha therapeutics in the setting of neuroinflammation.