Hashemizadeh Shiva, Gharaylou Zeinab, Hosseindoost Saereh, Sardari Maryam, Omidi Ameneh, Hosseini Ravandi Hassan, Hadjighassem Mahmoudreza
Brain and Spinal Cord Injury Research Center, Neuroscience Institute, Tehran University of Medical Sciences, Tehran, Iran.
School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran.
Front Pharmacol. 2022 Oct 19;13:932487. doi: 10.3389/fphar.2022.932487. eCollection 2022.
Ion disturbances are among the most remarkable deficits in spinal cord injury (SCI). GABA is an integral part of neural interaction. Action of the GABA receptor depends on the amount of intracellular chloride. Homeostasis of chloride is controlled by two co-transporters, NKCC1 and KCC2. Previous studies revealed that NKCC1 are disturbed in SCI. In this study, NKCC1 is highly expressed in the epicenter of the lesioned spinal cord at 3 hours after induction of the lesion and reached the peak around 6 hours after SCI. Bumetanide (2 and 4 mg/day), as a specific NKCC1 inhibitor, was used at 3 hours post SCI for 28 days. The functional recovery outcomes were measured by the Basso-Beattie-Bresnahan (BBB) locomotor rating scale, ladder walking test, and hot plate test. The rats that received bumetanide 4 mg/day exhibited improved recovery of locomotor function, reduction of NKCC1 gene expression, and upregulation of GAP protein levels 28 days post SCI. Histological tissue evaluations confirmed bumetanide's neuroprotective and regenerative effects. This study provides novel evidence for the benefits of bumetanide in early administration after SCI.
离子紊乱是脊髓损伤（SCI）中最显著的缺陷之一。γ-氨基丁酸（GABA）是神经相互作用的一个组成部分。GABA受体的作用取决于细胞内氯离子的含量。氯离子的稳态由两种协同转运蛋白，即钠-钾-氯协同转运蛋白1（NKCC1）和钾-氯协同转运蛋白2（KCC2）控制。先前的研究表明，SCI中NKCC1会受到干扰。在本研究中，损伤诱导后3小时，NKCC1在损伤脊髓的中心高度表达，并在SCI后约6小时达到峰值。布美他尼（2毫克/天和4毫克/天）作为一种特异性NKCC1抑制剂，在SCI后3小时使用，持续28天。通过Basso-Beattie-Bresnahan（BBB）运动评分量表、爬梯试验和热板试验来测量功能恢复结果。接受4毫克/天布美他尼治疗的大鼠在SCI后28天表现出运动功能恢复改善、NKCC1基因表达降低以及缝隙连接蛋白2（GAP2）水平上调。组织学评估证实了布美他尼的神经保护和再生作用。本研究为布美他尼在SCI后早期给药的益处提供了新的证据。
