A derivative of the CRMP2 binding compound lanthionine ketimine provides neuroprotection in a mouse model of cerebral ischemia.
A derivative of the CRMP2 binding compound lanthionine ketimine provides neuroprotection in a mouse model of cerebral ischemia.
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DOI：
10.1016/j.neuint.2012.09.013
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发表时间：
2012-12
影响因子：
4.2
通讯作者：
Shah, Zahoor A.
中科院分区：
文献类型：
--
作者：
Nada, Shadia E.;Tulsulkar, Jatin;Raghavan, Aparna;Hensley, Kenneth;Shah, Zahoor A.
蓝硫氨酸是一种新型的神经营养和神经保护小分子，在治疗神经退行性疾病方面显示出良好的前景。特别是，最近开发的一种被称为LKE(羊毛硫氨酸酮胺5-乙酯)的细胞渗透性羊毛硫氨酸衍生物在低纳摩尔浓度下促进轴突生长。LKE还具有神经保护、抗细胞凋亡和抗炎等特性。其对脑缺血的治疗潜力及其神经营养作用机制尚未完全阐明。这里，我们假设LKE的神经保护作用可能是通过诱导或调节CRMP2来实现的。我们发现，用LKE处理原代培养的小鼠神经元，对叔丁基氢过氧化氢诱导的神经元死亡有明显的保护作用，可能是通过上调CRMP2来实现的。同样，体内研究表明，LKE治疗前和/或治疗后保护小鼠免受永久性大脑中动脉远端闭塞(p-MCAO)的影响，这一点在治疗组的中风损害减少和功能结果的旋转棒、握力和神经功能缺失评分方面得到了证明。LKE预处理组小鼠大脑皮层CRMP2蛋白表达水平较高，提示LKE的神经保护作用可能依赖于CRMP2。LKE组裂解PARP活性降低，SERT1活性升高，提示LKE具有抗细胞凋亡作用。提示LKE具有治疗脑缺血的潜力，其部分保护机制可能部分归因于CRMP2介导的作用和PARP-1/SIRT-1的调节。
Lanthionines are novel neurotrophic and neuroprotective small molecules that show promise for the treatment of neurodegenerative diseases. In particular, a recently developed, cell permeable lanthionine derivative known as LKE (lanthionine ketimine 5-ethyl ester) promotes neurite growth at low nanomolar concentrations. LKE also has neuroprotective, anti-apoptotic, and anti-inflammatory properties. Its therapeutic potential in cerebral ischemia and its mechanisms of neurotrophic action remain to be fully elucidated. Here, we hypothesize that the neuroprotective actions of LKE could result from induction or modulation of CRMP2. We found that treating primary cultured mouse neurons with LKE provided significant protection against t-butyl hydroperoxide-induced neuronal death possibly through CRMP2 upregulation. Similarly, in-vivo studies showed that LKE pre and/or post-treatment protects mice against permanent distal middle cerebral artery occlusion (p-MCAO) as evidenced by lower stroke lesions and improved functional outcomes in terms of rotarod, grip strength and neurologic deficit scores in treated groups. Protein expression levels of CRMP2 were higher in brain cortices of LKE pretreated mice, suggesting that LKE’s neuroprotective activity may be CRMP2 dependent. Lower activity of cleaved PARP and higher activity of SERT1 was also observed in LKE treated group suggesting its anti-apoptotic properties. Our results suggest that LKE has potential as a therapeutic intervention in cerebral ischemia and that part of its protective mechanism may be attributed in- part to CRMP2 mediated action and PARP-1/SIRT-1 modulation.
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