CR8, a selective and potent CDK inhibitor, provides neuroprotection in experimental traumatic brain injury.
CR8, a selective and potent CDK inhibitor, provides neuroprotection in experimental traumatic brain injury.
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DOI：
10.1007/s13311-011-0095-4
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发表时间：
2012-04
影响因子：
5.7
通讯作者：
Faden, Alan I.
中科院分区：
文献类型：
--
作者：
Kabadi, Shruti V.;Stoica, Bogdan A.;Hanscom, Marie;Loane, David J.;Kharebava, Giorgi;Murray, Michael G., II;Cabatbat, Rainier M.;Faden, Alan I.
创伤性脑损伤（TBI）诱导继发性损伤机制，包括细胞周期激活（CCA），导致神经元死亡和神经功能障碍。我们最近报道，延迟给药roscovitine，一个相对选择性的细胞周期蛋白依赖性激酶（CDK）抑制剂，抑制CCA和减弱神经退行性变和功能缺陷后，控制性皮质撞击（CCI）损伤小鼠。在这里，我们使用小鼠CCI模型评估了CR8（一种更有效的第二代roscovitine类似物）的神经保护潜力。关键的CCA标记物（细胞周期蛋白A和B1）在TBI后损伤的皮质中显著上调，并且CDK底物的磷酸化增加。在TBI后以比先前对于roscovitine所需的剂量小20倍的剂量中央施用CR8，减弱CCA途径并且减少TBI后24小时的创伤后凋亡性细胞死亡。在TBI后3小时，CR8的中枢给药显著减弱了感觉运动和认知缺陷，减少了病变体积，并改善了皮质和齿状回中的神经元存活。此外，与相同模型中的roscovitine治疗不同，CR8还在第21天减弱了海马和丘脑的CA3区域中的创伤后神经变性。此外，以比先前所需的roscovitine低10倍的剂量延迟全身施用CR8，显著改善了CCI后的认知表现。这些发现进一步证明了实验性TBI后细胞周期抑制剂的神经保护潜力。鉴于CR8与早期的CDK抑制剂的嘌呤类似物类型相比具有更高的效力和功效，该药物应被视为未来TBI临床试验的候选药物。
Traumatic brain injury (TBI) induces secondary injury mechanisms, including cell cycle activation (CCA), that leads to neuronal death and neurological dysfunction. We recently reported that delayed administration of roscovitine, a relatively selective cyclin-dependent kinase (CDK) inhibitor, inhibits CCA and attenuates neurodegeneration and functional deficits following controlled cortical impact (CCI) injury in mice. Here we evaluated the neuro-protective potential of CR8, a more potent second-generation roscovitine analog, using the mouse CCI model. Key CCA markers (cyclin A and B1) were significantly up-regulated in the injured cortex following TBI, and phosphorylation of CDK substrates was increased. Central administration of CR8 after TBI, at a dose 20 times less than previously required for roscovitine, attenuated CCA pathways and reduced post-traumatic apoptotic cell death at 24 h post-TBI. Central administration of CR8, at 3 h after TBI, significantly attenuated sensorimotor and cognitive deficits, decreased lesion volume, and improved neuronal survival in the cortex and dentate gyrus. Moreover, unlike roscovitine treatment in the same model, CR8 also attenuated post-traumatic neurodegeneration in the CA3 region of the hippocampus and thalamus at 21 days. Furthermore, delayed systemic administration of CR8, at a dose 10 times less than previously required for roscovitine, significantly improved cognitive performance after CCI. These findings further demonstrate the neuroprotective potential of cell cycle inhibitors following experimental TBI. Given the increased potency and efficacy of CR8 as compared to earlier purine analog types of CDK inhibitors, this drug should be considered as a candidate for future clinical trials of TBI.
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影响因子：
2.5
作者：
Goldstein, LB
通讯作者：
Goldstein, LB
影响因子：
4.8
作者：
Copani, A;Condorelli, F;Sortino, MA
通讯作者：
Sortino, MA
影响因子：
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作者：
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Holtzman, DM
DOI：
10.1073/pnas.0500989102
发表时间：
2005-06-07
影响因子：
11.1
作者：
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通讯作者：
Faden, AI
DOI：
10.1097/ta.0b013e3181bbfe2a
发表时间：
2010-09-01
影响因子：
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作者：
Dutton, Richard P.;Stansbury, Lynn G.;Scalea, Thomas M.
通讯作者：
Scalea, Thomas M.