Cell cycle inhibition provides neuroprotection and reduces glial proliferation and scar formation after traumatic brain injury
Cell cycle inhibition provides neuroprotection and reduces glial proliferation and scar formation after traumatic brain injury
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DOI：
10.1073/pnas.0500989102
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发表时间：
2005-06-07
影响因子：
11.1
通讯作者：
Faden, AI
中科院分区：
文献类型：
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作者：
Di Giovanni, S;Movsesyan, V;Faden, AI
创伤性脑损伤 (TBI) 会导致神经元凋亡、炎症和反应性星形胶质细胞增生，从而导致继发性组织损失、再生受损和相关的功能障碍。在这里，我们发现细胞周期成分的上调与大鼠 TBI 后 caspase 介导的神经元凋亡和神经胶质增殖有关。在原代神经元和星形胶质细胞培养物中，细胞周期抑制（包括细胞周期蛋白依赖性激酶抑制剂黄吡醇、罗可维汀和奥洛穆辛）减少了细胞周期蛋白的上调，限制了依托泊苷诱导的 DNA 损伤后的神经元细胞死亡，并减弱了星形胶质细胞的增殖。大鼠 TBI 后，flavopiridol 降低同侧皮层和海马神经元和神经胶质细胞中细胞周期蛋白 D1 的表达。治疗还减少了神经元细胞死亡和病变体积，减少了星形胶质细胞疤痕形成和小胶质细胞激活，并改善了运动和认知恢复。细胞周期抑制能够减少实验性 TBI 后神经元细胞死亡和反应性神经胶质增生，这表明这种治疗方法可能在临床上有用。
Traumatic brain injury (TBI) causes neuronal apoptosis, inflammation, and reactive astrogliosis, which contribute to secondary tissue loss, impaired regeneration, and associated functional disabilities. Here, we show that up-regulation of cell cycle components is associated with caspase-mediated neuronal apoptosis and glial proliferation after TBI in rats. In primary neuronal and astrocyte cultures, cell cycle inhibition (including the cyclin-dependent kinase inhibitors flavopiridol, roscovitine, and olomoucine) reduced upregulation of cell cycle proteins, limited neuronal cell death after etoposide-induced DNA damage, and attenuated astrocyte proliferation. After TBI in rats, flavopiridol reduced cyclin D1 expression in neurons and glia in ipsilateral cortex and hippocampus. Treatment also decreased neuronal cell death and lesion volume, reduced astroglial scar formation and microglial activation, and improved motor and cognitive recovery. The ability of cell cycle inhibition to decrease both neuronal cell death and reactive gliosis after experimental TBI suggests that this treatment approach may be useful clinically.