中国神经再生研究(英文版) ›› 2015, Vol. 10 ›› Issue (12): 1924-1925.doi: 10.4103/1673-5374.172313

• 观点:神经损伤修复保护与再生 • 上一篇    下一篇

阳离子氯离子转运蛋白对神经系统疾病的药理学干预抑制与保护

  

  • 收稿日期:2015-11-10 出版日期:2015-12-30 发布日期:2015-12-30

Pharmacological inhibition of cation-chloride cotransporters for neurological diseases

Rachel Nepomuceno, Dandan Sun   

  1. Department of Neurology, University of Pittsburgh, Pittsburgh, PA, USA (Nepomuceno R, Sun D)
    Veterans Affairs Pittsburgh Health Care System, Geriatric Research, Educational and Clinical Center, Pittsburgh, PA, USA (Sun D)
  • Received:2015-11-10 Online:2015-12-30 Published:2015-12-30
  • Contact: Dandan Sun, M.D., Ph.D. sund@upmc.edu.

摘要:

美国匹兹堡大学医学院神经科学系Dandan Sun教授在发表于《中国神经再生研究(英文版)》2015年12期杂志中,总结了通过影响γ-氨基丁酸受体,质膜γ-氨基丁酸转运蛋白及分解酶γ-氨基丁酸转氨酶来改变γ-氨基丁酸神经递质的单体化合物的近期发展。发现γ-氨基丁酸神经递质的减少表明其参与一些神经系统疾病的发病病因。我们研究表明,阳离子氯转运蛋白药物抑制改善了CL-i稳态,并演示了恢复内源性γ-氨基丁酸能抑制和谷氨酸的兴奋性神经系统疾病神经回路的可能性。阳离子氯化物转运蛋白靶向药物,如布美他尼的使用可能减少缺血性中风二次离子的干扰并促进脑损伤后神经功能恢复。未来可以采用阳离子氯化物转运蛋白靶向发育大脑的药物的开发。

Abstract:

New clinical evidence suggests that pharmacological blockade of CCCs may improve [Cli] homeostasis dysregulation and restore endogenous GABAergic inhibition and glutamatergic excitability in neurological diseases with disturbed neuronal circuits, such as epilepsy and autism. The usage of the current CCC-targeting drugs in the preclinical studies, such as bumetanide, shows their potentials to reduce brain damage and accelerate neurological recovery in acute brain disorders that have secondary ionic disturbances including ischemic stroke. However, recent investigation of bumetanide pharmokinetics
shows rapid elimination and poor brain penetration, which may lead to negative side effects, such as clinical deficits in hearing and developmental delay in mice. Additional investigation of the long-term effects of the current CCC targeting drugs in the immature brain is warranted. Developing more selective and potent inhibitors of the CCCs with less adverse side effects is needed. Better understanding of roles of NKCC1 in the neurological diseases may lead to new alternative and more effective therapies.