Keilhoff Gerburg, Schild Lorenz, Fansa Hisham
Institute of Medical Neurobiology, University of Magdeburg, Leipziger Strasse 44, D-39120 Magdeburg, Germany.
Exp Neurol. 2008 Jul;212(1):189-200. doi: 10.1016/j.expneurol.2008.03.028. Epub 2008 Apr 15.
Minocycline, a broad-spectrum antimicrobial tetracycline, acts neuroprotectively in ischemia. Recently, however, minocycline has been revealed to have ambiguous effects on nerve regeneration. Thus its effects in a rat sciatic nerve transplantation model and on cultivated Schwann cells stressed by oxygen glucose deprivation (OGD) were studied. The negative effect of minocycline on Wallerian degeneration, the essential initial phase of degeneration/regeneration after nerve injury, that was recently demonstrated, was excluded by using predegenerated nerve and Schwann cell-enriched muscle grafts, both free of Wallerian degeneration. They were compared with common nerve grafts. The principle findings were that in vitro minocycline provided protective effects against OGD-induced death of Schwann cells by preventing permeability of the mitochondrial membrane. It suppressed the OGD-mediated induction of HIF-1alpha and BAX, and stabilized/induced BCL-2. Cytochrome c release and cleavage of procaspase-3 were diminished; release and translocation of AIF and cytotoxic cleavage of actin into fractin were stopped. In common nerve grafts, minocycline, besides its direct anti-ischemic effect, hampered revascularization by down-regulation of MMP9 and VEGF prolonging ischemia and impeding macrophage recruitment. In bioartificial nerve grafts that were free of Wallerian degeneration and revealed lower immunogenicity, minocycline aided the regeneration process. Here, the direct anti-ischemic effect of minocycline on Schwann cells, which are mandatory for successful peripheral nerve regeneration, dominated the systemic anti-angiogenic/pro-ischemic effects. In common nerve grafts, however, where Wallerian degeneration is a prerequisite, the anti-angiogenic and macrophage-depressing effect is an obstacle for regeneration.
米诺环素是一种广谱抗菌四环素，在缺血中具有神经保护作用。然而，最近发现米诺环素对神经再生的影响尚不明确。因此，研究了其在大鼠坐骨神经移植模型以及对氧糖剥夺（OGD）应激的培养雪旺细胞中的作用。通过使用预先变性的神经和富含雪旺细胞的肌肉移植物（两者均无沃勒变性），排除了米诺环素对沃勒变性（神经损伤后变性/再生的关键初始阶段）的负面影响，将它们与普通神经移植物进行比较。主要发现是，在体外，米诺环素通过防止线粒体膜通透性，对OGD诱导的雪旺细胞死亡具有保护作用。它抑制了OGD介导的HIF-1α和BAX的诱导，并稳定/诱导了BCL-2。细胞色素c的释放和procaspase-3的裂解减少；AIF的释放和转位以及肌动蛋白向fractin的细胞毒性裂解停止。在普通神经移植物中，米诺环素除了具有直接的抗缺血作用外，还通过下调MMP9和VEGF来阻碍血管再生，延长缺血时间并阻碍巨噬细胞募集。在无沃勒变性且免疫原性较低的生物人工神经移植物中，米诺环素有助于再生过程。在这里，米诺环素对雪旺细胞的直接抗缺血作用（这是成功进行周围神经再生所必需的）主导了全身抗血管生成/促缺血作用。然而，在以沃勒变性为前提条件的普通神经移植物中，抗血管生成和抑制巨噬细胞的作用是再生的障碍。
