Delayed treatment with systemic (S)-roscovitine provides neuroprotection and inhibits in vivo CDK5 activity increase in animal stroke models.
Delayed treatment with systemic (S)-roscovitine provides neuroprotection and inhibits in vivo CDK5 activity increase in animal stroke models.
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DOI：
10.1371/journal.pone.0012117
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发表时间：
2010-08-12
期刊：
影响因子：
3.7
通讯作者：
Timsit S
中科院分区：
文献类型：
--
作者：
Menn B;Bach S;Blevins TL;Campbell M;Meijer L;Timsit S
尽管具有挑战性，但缺血性卒中的神经保护治疗仍然是对抗缺血性损伤机制和减少脑组织损伤的一种有趣的策略。在潜在的神经保护药物中，细胞周期蛋白依赖性激酶（CDK）抑制剂是有趣的治疗候选药物。越来越多的证据无可争议地将细胞周期CDKs和CDK5与中风的发病机制联系起来。尽管最近的研究已经在相关的动物模型中证明了药理CDK抑制剂有很好的神经保护作用，但它们都与人类治疗没有临床相关性。在本研究中，我们报告了(S)-罗斯科维汀（一种众所周知的有丝分裂CDKs和CDK5抑制剂）在两种局灶性缺血模型中以剂量依赖的方式具有神经保护作用，这是STAIR指南所推荐的。我们发现(S)-罗斯科维汀能够穿过血脑屏障。(S)-罗斯科维汀在损伤后2小时系统给药后仍有显著的体内阳性作用。此外，我们还验证了(S)-罗斯科维汀在缺血后的体内靶点。脑损伤后3小时观察到CDK5/p25活性增加，并通过全身(S)-罗斯科维汀给予预防。因此，我们的研究结果表明，罗斯科维汀可能通过CDK5依赖机制保护体内神经元。总之，我们的数据为进一步开发药物CDK抑制剂用于中风治疗提供了新的证据。
Although quite challenging, neuroprotective therapies in ischemic stroke remain an interesting strategy to counter mechanisms of ischemic injury and reduce brain tissue damage. Among potential neuroprotective drug, cyclin-dependent kinases (CDK) inhibitors represent interesting therapeutic candidates. Increasing evidence indisputably links cell cycle CDKs and CDK5 to the pathogenesis of stroke. Although recent studies have demonstrated promising neuroprotective efficacies of pharmacological CDK inhibitors in related animal models, none of them were however clinically relevant to human treatment. In the present study, we report that systemic delivery of (S)-roscovitine, a well known inhibitor of mitotic CDKs and CDK5, was neuroprotective in a dose-dependent manner in two models of focal ischemia, as recommended by STAIR guidelines. We show that (S)-roscovitine was able to cross the blood brain barrier. (S)-roscovitine significant in vivo positive effect remained when the compound was systemically administered 2 hrs after the insult. Moreover, we validate one of (S)-roscovitine in vivo target after ischemia. Cerebral increase of CDK5/p25 activity was observed 3 hrs after the insult and prevented by systemic (S)-roscovitine administration. Our results show therefore that roscovitine protects in vivo neurons possibly through CDK5 dependent mechanisms. Altogether, our data bring new evidences for the further development of pharmacological CDK inhibitors in stroke therapy.
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DOI：
10.1111/j.1432-1033.1997.t01-2-00527.x
发表时间：
1997-01-15
期刊：
EUROPEAN JOURNAL OF BIOCHEMISTRY
影响因子：
--
作者：
Meijer, L;Borgne, A;Moulinoux, JP
通讯作者：
Moulinoux, JP
DOI：
10.1073/pnas.170144197
发表时间：
2000-08-29
影响因子：
11.1
作者：
Osuga, H;Osuga, S;Park, DS
通讯作者：
Park, DS
影响因子：
8.3
作者：
Fisher M;Feuerstein G;Howells DW;Hurn PD;Kent TA;Savitz SI;Lo EH;STAIR Group
通讯作者：
STAIR Group
影响因子：
5.3
作者：
Katchanov, J;Harms, C;Endres, M
通讯作者：
Endres, M
影响因子：
11.2
作者：
O'Collins, VE;Macleod, MR;Howells, DW
通讯作者：
Howells, DW