Imbalanced Subthreshold Currents Following Sepsis and Chemotherapy: A Shared Mechanism Offering a New Therapeutic Target?
Imbalanced Subthreshold Currents Following Sepsis and Chemotherapy: A Shared Mechanism Offering a New Therapeutic Target?
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DOI：
10.1177/1073858420981866
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发表时间：
2022-04
期刊：
影响因子：
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通讯作者：
Cope TC
中科院分区：
文献类型：
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作者：
Rich MM;Housley SN;Nardelli P;Powers RK;Cope TC
众所周知，脓毒症和癌症化疗都会导致神经功能障碍。两组患者的主要缺陷是神经病和脑病。其根本机制尚不清楚。对这些不同病症的临床前模型的分析揭示了导致周围神经病变的离子通道功能的类似缺陷。离子通道功能的缺陷延伸到中枢神经系统，下部运动神经元受到影响。在运动神经元中，缺陷涉及负责亚阈值电流的离子通道，该亚阈值电流将稳定的去极化转化为重复放电。无法正确地将去极化转化为稳定、重复的放电会对运动功能产生深远的影响，并且可能是导致两组患者感到虚弱和疲劳的重要原因。功能破坏可能是神经变性的替代或补充，可能是虚弱和疲劳的基础，这导致了一种新的治疗方法。脓毒症大鼠模型中血清素 (5HT) 受体的激活可恢复阈下电流和正常运动神经元放电的正常平衡。如果其他中枢神经系统神经元也出现阈下电流不平衡，则可能导致脑病。我们假设，从药理学上恢复阈下电流的适当平衡可能为从脓毒症或化疗中恢复的患者的神经病和脑病提供有效的治疗。
Both sepsis and treatment of cancer with chemotherapy are known to cause neurologic dysfunction. The primary defects seen in both groups of patients are neuropathy and encephalopathy; the underlying mechanisms are poorly understood. Analysis of preclinical models of these disparate conditions reveal similar defects in ion channel function contributing to peripheral neuropathy. The defects in ion channel function extend to the central nervous system where lower motoneurons are affected. In motoneurons the defect involves ion channels responsible for subthreshold currents that convert steady depolarization into repetitive firing. The inability to correctly translate depolarization into steady, repetitive firing has profound effects on motor function, and could be an important contributor to weakness and fatigue experienced by both groups of patients. The possibility that disruption of function, either instead of, or in addition to neurodegeneration, may underlie weakness and fatigue leads to a novel approach to therapy. Activation of serotonin (5HT) receptors in a rat model of sepsis restores the normal balance of subthreshold currents and normal motoneuron firing. If an imbalance of subthreshold currents also occurs in other central nervous system neurons, it could contribute to encephalopathy. We hypothesize that pharmacologically restoring the proper balance of subthreshold currents might provide effective therapy for both neuropathy and encephalopathy in patients recovering from sepsis or treatment with chemotherapy.
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影响因子：
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作者：
Aaronson, Neil K;Mattioli, Vittorio;Minton, Ollie;Weis, Joachim;Johansen, Christoffer;Dalton, Susanne O;Verdonck-de Leeuw, Irma M;Stein, Kevin D;Alfano, Catherine M;Mehnert, Anja;de Boer, Angela;van de Poll-Franse, Lonneke V
通讯作者：
van de Poll-Franse, Lonneke V
影响因子：
3.8
作者：
Briani, Chiara;Argyriou, Andreas A.;Kalofonos, Haralabos P.
通讯作者：
Kalofonos, Haralabos P.
影响因子：
5.8
作者：
Avan, Abolfazl;Postma, Tjeerd J.;Peters, Godefridus J.
通讯作者：
Peters, Godefridus J.
影响因子：
4.5
作者：
Chatelier, Aurelien;Zhao, Juan;Chahine, Mohamed
通讯作者：
Chahine, Mohamed
DOI：
10.1038/nrclinonc.2012.88
发表时间：
2012-05-29
期刊：
Nature reviews. Clinical oncology
影响因子：
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作者：
通讯作者：
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