Mcdonald J W, Stefovska V G, Liu X Z, Shin H, Liu S, Choi D W
Department of Neurology, Washington University School of Medicine, PO Box 8111, 660 S Euclid Avenue, St Louis, MO 63110-1093, , USA.
Neuroscience. 2002;115(3):931-9. doi: 10.1016/s0306-4522(02)00342-1.
Previous studies have shown that pretreatment with neurotrophins can potentiate the vulnerability of cultured neurons to excitotoxic and free radical-induced necrosis, in contrast to their well known neuroprotective effects against apoptosis. Here we tested the hypothesis that this unexpected injury-potentiating effect of neurotrophins would also take place in the adult rat spinal cord. Fe(3+)-citrate was injected stereotaxically into spinal cord gray matter in adult rats in amounts sufficient to produce minimal tissue injury 24 h later. Twenty-four-hour pretreatment with brain-derived neurotrophic factor, neurotrophin-3, or neurotrophin-4/5, but not nerve growth factor, markedly enhanced tissue injury in the gray matter as evidenced by an increase in the damaged area, as well as the loss of neurons and oligodendrocytes. Consistent with maintained free radical mediation, the neurotrophin-potentiated iron-induced spinal cord damage was blocked by co-application of the antioxidant N-tert-butyl-(2-sulfophenyl)-nitrone. These data support the hypothesis that the overall neuroprotective properties of neurotrophins in models of acute injury to the spinal cord may be limited by an underlying potentiation of free radical-mediated necrosis.
先前的研究表明，与神经营养因子对凋亡具有众所周知的神经保护作用相反，用其进行预处理可增强培养的神经元对兴奋性毒性和自由基诱导的坏死的易感性。在此，我们检验了这样一个假说，即神经营养因子这种意外的损伤增强作用在成年大鼠脊髓中也会发生。将柠檬酸铁（Fe(3+)）立体定向注射到成年大鼠脊髓灰质中，注射量足以在24小时后产生最小程度的组织损伤。用脑源性神经营养因子、神经营养因子-3或神经营养因子-4/5进行24小时预处理，但不用神经生长因子，可显著增强灰质中的组织损伤，受损面积增加以及神经元和少突胶质细胞丢失证明了这一点。与自由基介导作用持续存在一致，神经营养因子增强的铁诱导的脊髓损伤可通过共同应用抗氧化剂N-叔丁基-（2-磺苯基）-硝酮来阻断。这些数据支持这样的假说，即在脊髓急性损伤模型中，神经营养因子的整体神经保护特性可能会受到自由基介导的坏死的潜在增强作用的限制。
