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In vivo KPT-350 treatment decreases cortical hyperexcitability following traumatic brain injury.
Brain Injury ( IF 1.5 ) Pub Date : 2020-08-27 , DOI: 10.1080/02699052.2020.1807056
David Cantu 1 , Danielle Croker 1 , Sharon Shacham 2 , Sharon Tamir 2 , Chris Dulla 1
Affiliation  

Primary Objective

We tested whether KPT-350, a novel selective inhibitor of nuclear export, could attenuate cortical network hyperexcitability, a major risk factor for developing post-traumatic epilepsy (PTE) following traumatic brain injury (TBI).

Research Design

All mice in this study underwent TBI and were subsequently treated with either KPT-350 or vehicle during the post-injury latent period. Half of the animal cohort was used for electrophysiology while the other half was used for immunohistochemical analysis.

Methods and Procedures

TBI was induced using the controlled cortical impact (CCI) model. Cortical network activity was recorded by evoking field potentials from deep layers of the cortex and analyzed using Matlab software. Immunohistochemistry coupled with fluorescence microscopy and Image J analysis detected changes in neuronal and glial markers.

Main Outcomes and Results

KPT-350 attenuated TBI-associated epileptiform activity and restored disrupted input-output responses in cortical brain slices. In vivo KPT-350 treatment reduced the loss of parvalbumin-(+) GABAergic interneurons after CCI but did not significantly change CCI-induced loss of somatostatin-(+) GABAergic interneurons, nor did it reduce reactivity of GFAP and Iba1 glial markers.

Conclusion

KPT-350 can prevent cortical hyperexcitability and reduce the loss of parvalbumin-(+) GABAergic inhibitory neurons, making it a potential therapeutic option for preventing PTE.



中文翻译:

体内KPT-350治疗可降低颅脑外伤后皮质过度兴奋性。

主要目标

我们测试了KPT-350(一种新型的核输出选择性抑制剂)是否可以减弱皮层网络的过度兴奋性,后者是颅脑外伤(TBI)后发生创伤后癫痫(PTE)的主要危险因素。

研究设计

这项研究中的所有小鼠均接受了TBI治疗,随后在伤后潜伏期接受了KPT-350或赋形剂的治疗。动物队列的一半用于电生理,另一半用于免疫组织化学分析。

方法与程序

TBI是使用可控皮层撞击(CCI)模型诱导的。通过唤起皮质深层的场电位来记录皮质网络活动,并使用Matlab软件进行分析。免疫组织化学结合荧光显微镜和Image J分析检测到神经元和神经胶质标志物的变化。

主要结果和结果

KPT-350减弱了TBI相关的癫痫样活动,并恢复了皮质脑切片中中断的输入输出反应。体内KPT-350治疗减少了CCI后小白蛋白-(+)GABA能神经元的损失,但并未显着改变CCI诱导的生长抑素-(+)GABA能神经元的损失,也没有降低GFAP和Iba1神经胶质标志物的反应性。

结论

KPT-350可以防止皮质过度兴奋,并减少小白蛋白-(+)GABA能抑制神经元的损失,使其成为预防PTE的潜在治疗选择。

更新日期:2020-09-23
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