Minocycline inhibits contusion-triggered mitochondrial cytochrome c release and mitigates functional deficits after spinal cord injury
Minocycline inhibits contusion-triggered mitochondrial cytochrome c release and mitigates functional deficits after spinal cord injury
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DOI：
10.1073/pnas.0306239101
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发表时间：
2004-03-02
影响因子：
11.1
通讯作者：
Friedlander, RM
中科院分区：
文献类型：
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作者：
Teng, YD;Choi, H;Friedlander, RM
我们研究了通透性过渡介导的线粒体细胞色素c释放是否是治疗急性脊髓损伤（SCI）的潜在治疗靶点。根据先前的报道，二甲胺四环素是第二代四环素，部分通过抑制线粒体细胞色素c的释放和反应性小胶质细胞增生来发挥神经保护作用。我们首先评估大鼠T10挫伤性脊髓损伤后损伤中心的细胞色素c释放。细胞色素c释放在损伤后约4-8小时达到峰值。一项剂量反应研究产生了一种安全的药理学方案，使i.p.米诺环素在脊髓损伤后4小时显著降低中心的胞浆细胞色素c。在长期研究中，相对于对照组，i.p.米诺环素（在脊髓损伤后1小时给药90 mg/kg，然后每12小时给药45 mg/kg，持续5天）显著增强了长期后肢运动。协调运动功能和后肢反射恢复也有明显改善。组织病理学显示二甲胺四环素治疗减轻了后期组织损失，显著保留了震中附近的白质和腹角运动神经元。此外，胶质纤维酸性蛋白和2‘,3’环核苷酸3'磷酸二酯酶免疫细胞化学显示明显减少星形胶质细胞，提高少突胶质细胞的存活率。因此，线粒体细胞色素c的释放是脊髓损伤的重要继发性损伤机制。在对抗这一过程和小胶质瘤方面具有多方面作用的药物可能保护一定比例的脊髓组织，这对功能恢复具有临床意义。米诺环素具有临床证明的安全性、穿越血脑屏障的能力以及在临床相关治疗窗口期显示的疗效，可能成为急性脊髓损伤的有效治疗药物。
We investigated whether permeability transition-mediated release of mitochondrial cytochrome c is a potential therapeutic target for treating acute spinal cord injury (SCI). Based on previous reports, minocycline, a second-generation tetracycline, exerts neuroprotection partially by inhibiting mitochondrial cytochrome c release and reactive microgliosis. We first evaluated cytochrome c release at the injury epicenter after a T10 contusive SCI in rats. Cytochrome c release peaked at approximate to4-8 h postinjury. A dose-response study generated a safe pharmacological regimen that enabled i.p. minocycline to significantly lower cytosolic cytochrome c at the epicenter 4 h after SCI. In the long-term study, i.p. minocycline (90 mg/kg administered 1 h after SCI followed by 45 mg/kg administered every 12 h for 5 days) markedly enhanced long-term hind limb locomotion relative to that of controls. Coordinated motor function and hind limb reflex recoveries also were improved significantly. Histopathology suggested that minocycline treatment alleviated later-phase tissue loss, with significant sparing of white matter and ventral horn motoneurons at levels adjacent to the epicenter. Furthermore, glial fibrillary acidic protein and 2',3' cyclic nucleotide 3' phosphodiesterase immunocytochemistry showed an evident reduction in astrogliosis and enhanced survival of oligodendrocytes. Therefore, release of mitochondrial cytochrome c is an important secondary injury mechanism in SCI. Drugs with multifaceted effects in antagonizing this process and microgliosis may protect a proportion of spinal cord tissue that is clinically significant for functional recovery. Minocycline, with its proven clinical safety, capability to cross the blood-brain barrier, and demonstrated efficacy during a clinically relevant therapeutic window, may become an effective therapy for acute SCI.