Pharmacological approaches to repair the injured spinal cord
Pharmacological approaches to repair the injured spinal cord
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DOI：
10.1089/neu.2006.23.318
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发表时间：
2006-03-01
影响因子：
4.2
通讯作者：
Fehlings, MG
中科院分区：
文献类型：
--
作者：
Baptiste, DC;Fehlings, MG
急性创伤性脊髓损伤(SCI)会导致损伤平面以下的神经功能的毁灭性丧失，并对体内多个系统产生不利影响。脊髓损伤的病理生物学涉及对脊髓的原发机械性损伤和一系列延迟的继发性事件的激活，最终导致脊髓的进行性退化。机械损伤所致的细胞死亡以坏死为主，继发性损伤事件则触发了一系列的细胞死亡机制。这些继发性事件包括血管异常、缺血-再灌注、谷氨酸兴奋毒性和离子平衡紊乱、氧化细胞损伤和强烈的炎症反应。脊髓损伤的黄金标准疗法尚未建立，尽管甲基强的松龙(NASCIS II和III)和GM-1神经节苷脂(马里兰和赛根)的临床试验表明疗效不大，尽管潜在的重要治疗效果。鉴于脊髓损伤对个体的巨大影响，迫切需要其他治疗干预措施。目前，许多有希望的药物治疗方法正在研究脊髓损伤动物模型的神经保护能力。这些药物包括钠(Na+)通道阻滞剂利鲁唑、四环素衍生物米诺环素、FusoGen共聚物聚乙二醇(PEG)和组织保护性激素促红细胞生成素(EPO)。此外，目前正在进行临床试验，研究Rho通路拮抗剂Cethrin(R)(BioAxone治疗公司)和激活的自体巨噬细胞(ProCord(R)；Proneuron BioTechnologies)在胸部和颈部脊髓损伤患者中的假定神经保护和神经再生特性。我们预计，这些研究将唤起人们对转化性临床试验重新产生兴趣的时代。归根结底，由于创伤性脊髓损伤的多因素病理生理学，有效的治疗将需要综合治疗。
Acute traumatic spinal cord injury (SCI) results in a devastating loss of neurological function below the level of injury and adversely affects multiple systems within the body. The pathobiology of SCI involves a primary mechanical insult to the spinal cord and activation of a delayed secondary cascade of events, which ultimately causes progressive degeneration of the spinal cord. Whereas cell death from the mechanical injury is predominated by necrosis, secondary injury events trigger a continuum of necrotic and apoptotic cell death mechanisms. These secondary events include vascular abnormalities, ischemia-reperfusion, glutamate excitotoxicity and disturbances in ionic homeostasis, oxidative cell injury, and a robust inflammatory response. No gold standard therapy for SCI has been established, although clinical trials with methylprednisolone (NASCIS II and III) and GM-1 ganglioside (Maryland and Sygen) have demonstrated modest, albeit potentially important therapeutic benefits. In light of the overwhelming impact of SCI on the individual, other therapeutic interventions are urgently needed. A number of promising pharmacological therapies are currently under investigation for neuroprotective abilities in animal models of SCI. These include the sodium (Na+) channel blocker riluzole, the tetracycline derivative minocycline, the fusogen copolymer polyethylene glycol (PEG), and the tissue-protective hormone erythropoietin (EPO). Moreover, clinical trials investigating the putative neuroprotective and neuroregenerative properties ascribed to the Rho pathway antagonist, Cethrin (R) (BioAxone Therapeutic, Inc.), and implantation of activated autologous macrophages (ProCord (R); Proneuron Biotechnologies) in patients with thoracic and cervical SCI are now underway. We anticipate that these studies will harken an era of renewed interest in translational clinical trials. Ultimately, due to the multi-factorial pathophysiology of traumatic SCI, effective therapies will require combined approaches.