"Calcium bombs" as harbingers of synaptic pathology and their mitigation by magnesium at murine neuromuscular junctions.
"Calcium bombs" as harbingers of synaptic pathology and their mitigation by magnesium at murine neuromuscular junctions.
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DOI：
10.3389/fnmol.2022.937974
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发表时间：
2022
影响因子：
4.8
通讯作者：
Ribchester, Richard R.
中科院分区：
文献类型：
--
作者：
Dissanayake, Kosala N.;Redman, Robert R.;Mackenzie, Harry;Eddleston, Michael;Ribchester, Richard R.
关键词：
兴奋毒性被认为是肌萎缩侧索硬化症（ALS）发病和进展的重要因素。来自人类和动物研究的证据还表明，ALS的早期体征包括在运动神经元细胞体变性之前，神经肌肉接头（NMJ）处的运动神经末梢的变性。在这里，我们使用了一个模型的兴奋性毒性在NMJ在离体小鼠肌肉，利用有机磷（OP）化合物氧化乐果，抑制乙酰胆碱酯酶活性。急性暴露于氧乐果（100 μM）诱导运动终板对20-50 Hz短暂强直神经刺激的反应延长。在某些肌纤维中，Fluo-4荧光显示这些挛缩与运动终板中Ca 2+（“钙弹”）的爆炸性增加有关。钙弹强烈和选择性地减轻增加镁离子浓度从1到5毫米。过夜培养的神经肌肉制剂从WLDS小鼠氧乐果或其他OP杀虫剂成分及其代谢产物（乐果，环己酮，环己醇）诱导变性的NMJ。这种退化也强烈减轻增加[Mg 2 +]从1到5 mM。因此，等效的增加细胞外[Mg 2 +]减轻突触后钙弹和变性的NMJ。这些数据支持Ca 2+与NMJ兴奋性毒性之间的联系，并表明升高细胞外[Mg 2 +]可能是治疗兴奋性毒性触发物诱导的突触病理学的有效干预。
Excitotoxicity is thought to be an important factor in the onset and progression of amyotrophic lateral sclerosis (ALS). Evidence from human and animal studies also indicates that early signs of ALS include degeneration of motor nerve terminals at neuromuscular junctions (NMJs), before degeneration of motor neuron cell bodies. Here we used a model of excitotoxicity at NMJs in isolated mouse muscle, utilizing the organophosphorus (OP) compound omethoate, which inhibits acetylcholinesterase activity. Acute exposure to omethoate (100 μM) induced prolonged motor endplate contractures in response to brief tetanic nerve stimulation at 20–50 Hz. In some muscle fibers, Fluo-4 fluorescence showed association of these contractures with explosive increases in Ca2+ (“calcium bombs”) localized to motor endplates. Calcium bombs were strongly and selectively mitigated by increasing Mg2+ concentration in the bathing medium from 1 to 5 mM. Overnight culture of nerve-muscle preparations from WldS mice in omethoate or other OP insecticide components and their metabolites (dimethoate, cyclohexanone, and cyclohexanol) induced degeneration of NMJs. This degeneration was also strongly mitigated by increasing [Mg2+] from 1 to 5 mM. Thus, equivalent increases in extracellular [Mg2+] mitigated both post-synaptic calcium bombs and degeneration of NMJs. The data support a link between Ca2+ and excitotoxicity at NMJs and suggest that elevating extracellular [Mg2+] could be an effective intervention in treatment of synaptic pathology induced by excitotoxic triggers.
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影响因子：
4.5
作者：
Eddleston, Michael;Street, Jonathan M.;Clutton, R. Eddie
通讯作者：
Clutton, R. Eddie
影响因子：
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影响因子：
3.3
作者：
Dissanayake, Kosala N.;Chou, Robert Chang-Chih;Ribchester, Richard R.
通讯作者：
Ribchester, Richard R.
影响因子：
5.3
作者：
Brown, Rosalind;Dissanayake, Kosala N.;Skehel, Paul A.;Ribchester, Richard R.
通讯作者：
Ribchester, Richard R.
影响因子：
5.5
作者：
Dissanayake，Kosala N.;Margetiny，Filip;Ribchester，Richard R.
通讯作者：
Ribchester，Richard R.