Lucius R, Sievers J
Anatomisches Institut der Universität Kiel, Germany.
Brain Res Mol Brain Res. 1997 Aug;48(1):181-4. doi: 10.1016/s0169-328x(97)00170-8.
In the developing central nervous system (CNS), the differentiation of neurons is accompanied by a large amount of cell loss in the form of programmed cell death (apoptosis). On the other hand, injury in the adult CNS often results in permanent neuronal degeneration leading to the failure of axonal regeneration. This could be related to an axotomy-induced activation of an apoptotic program. The interleukin-1beta-converting enzyme family of proteases has been implicated in playing a fundamental role in apoptotic processes in both invertebrates and vertebrates. In order to determine what role, if any, inhibitors of the interleukin-1beta-converting enzyme family might play in axonal regeneration after axotomy we employed an in vitro system using retinal explants from post-natal rats at the age between 9 and 12 days [R. Lucius, P. Young, S. Tidow and J. Sievers, Growth stimulation and chemotropic attraction of retinal ganglion cell axons in vitro by co-cultured optic nerves, astrocytes and astrocyte conditioned medium, Int. J. Dev. Neurosci., Vol. 14 (1996) 387-398]. The retinal ganglion cells in this model are comparable to adult animals in their regenerative response (D. Alcutt, M. Berry and J. Sievers, A qualitative comparison of the reaction of retinal ganglion cells to optic nerve crush in neonatal and adult mice, Dev. Brain Res., Vol. 16 (1984a) 231-240; D. Allcutt, M. Berry and J. Sievers, A quantitative comparison of the reaction of retinal ganglion cells to optic nerve crush in neonatal and adult mice, Dev. Brain Res., Vol. 16 (1984b) 219-230]. The addition of the synthetic peptide inhibitor YVAD (Ac-Tyr-Val-Ala-Asp-aldehyde), which reversible inhibits interleukin-1beta-converting enzyme and subsequent apoptosis, enhances the number and length of regenerating neurites of retinal ganglion cells. However, this manipulation was not able to overcome free radical-induced axonal degeneration/neuronal apoptosis, suggesting at least two different death pathways leading to neuronal degeneration/cell death. These results provide the first evidence that inhibitors of key enzymes of the apoptotic program could play a beneficial role to overcome neurite degeneration after axotomy in the adult mammalian CNS.
在发育中的中枢神经系统（CNS）中，神经元的分化伴随着大量以程序性细胞死亡（凋亡）形式出现的细胞损失。另一方面，成年CNS中的损伤常常导致永久性神经元变性，进而导致轴突再生失败。这可能与轴突切断诱导的凋亡程序激活有关。白细胞介素-1β转换酶家族蛋白酶在无脊椎动物和脊椎动物的凋亡过程中均被认为起着重要作用。为了确定白细胞介素-1β转换酶家族抑制剂在轴突切断后的轴突再生中可能发挥何种作用（如果有作用的话），我们采用了一种体外系统，使用出生后9至12天的大鼠视网膜外植体[R. Lucius, P. Young, S. Tidow和J. Sievers，《共培养的视神经、星形胶质细胞和星形胶质细胞条件培养基对视网膜神经节细胞轴突的生长刺激和趋化吸引》，《国际发育神经科学杂志》，第14卷（1996年），第387 - 398页]。该模型中的视网膜神经节细胞在其再生反应方面与成年动物相当（D. Alcutt, M. Berry和J. Sievers，《新生小鼠和成年小鼠视网膜神经节细胞对视神经挤压反应的定性比较》，《发育脑研究》，第16卷（1984a），第231 - 240页；D. Allcutt, M. Berry和J. Sievers，《新生小鼠和成年小鼠视网膜神经节细胞对视神经挤压反应的定量比较》，《发育脑研究》，第16卷（1984b），第219 - 230页]。添加合成肽抑制剂YVAD（Ac-Tyr-Val-Ala-Asp-醛），其可可逆性抑制白细胞介素-1β转换酶及随后的凋亡，可增加视网膜神经节细胞再生神经突的数量和长度。然而，这种操作无法克服自由基诱导的轴突变性/神经元凋亡，这表明至少存在两条不同的导致神经元变性/细胞死亡的死亡途径。这些结果首次证明，凋亡程序关键酶的抑制剂在克服成年哺乳动物CNS轴突切断后的神经突变性方面可能发挥有益作用。
