Homocysteine aggravates ROS-induced depression of transmitter release from motor nerve terminals: potential mechanism of peripheral impairment in motor neuron diseases associated with hyperhomocysteinemia.
Homocysteine aggravates ROS-induced depression of transmitter release from motor nerve terminals: potential mechanism of peripheral impairment in motor neuron diseases associated with hyperhomocysteinemia.
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DOI：
10.3389/fncel.2015.00391
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发表时间：
2015
影响因子：
5.3
通讯作者：
Giniatullin R
中科院分区：
文献类型：
--
作者：
Bukharaeva E;Shakirzyanova A;Khuzakhmetova V;Sitdikova G;Giniatullin R
同型半胱氨酸 (HCY) 是一种促炎性含硫氧化还原活性内源性氨基酸，其浓度在包括肌萎缩侧索硬化症 (ALS) 在内的神经退行性疾病中增加。一种广泛持有的观点认为，HCY 可能通过促进氧化应激而导致神经退行性变。然而，目前尚未研究HCY对运动神经末梢的作用。我们之前报道过氧化应激抑制神经肌肉接头处的突触传递，主要针对运动神经末梢。在当前的研究中，我们研究了 HCY 对氧化应激引起的小鼠膈肌递质释放损伤的影响。温和的氧化剂 H2O2 降低了神经末梢自发量子释放的强度（以微型终板电位 MEPP 的频率测量），而 MEPP 的幅度没有变化，表明存在突触前效应。用 HCY 预处理 2 小时仅轻微影响 MEPP 的幅度和频率，但使 H2O2 的抑制效力增加了近两倍。由于 HCY 可以激活谷氨酸 N-甲基 D-天冬氨酸 (NMDA) 受体的某些亚型，因此我们测试了 NMDA 受体在 HCY 致敏作用中的作用。值得注意的是，NMDA 受体的选择性阻断剂 AP-5 完全消除了 HCY 对 H2O2 诱导的突触前抑制作用的敏化作用。因此，在哺乳动物神经肌肉接头处，HCY 通过 NMDA 受体激活，很大程度上增加了氧化应激对递质释放的抑制作用。 HCY 和局部氧化应激的联合作用尤其会导致神经退行性运动神经元疾病（包括 ALS）中突触前末梢的损伤。
Homocysteine (HCY) is a pro-inflammatory sulphur-containing redox active endogenous amino acid, which concentration increases in neurodegenerative disorders including amyotrophic lateral sclerosis (ALS). A widely held view suggests that HCY could contribute to neurodegeneration via promotion of oxidative stress. However, the action of HCY on motor nerve terminals has not been investigated so far. We previously reported that oxidative stress inhibited synaptic transmission at the neuromuscular junction, targeting primarily the motor nerve terminals. In the current study, we investigated the effect of HCY on oxidative stress-induced impairment of transmitter release at the mouse diaphragm muscle. The mild oxidant H2O2 decreased the intensity of spontaneous quantum release from nerve terminals (measured as the frequency of miniature endplate potentials, MEPPs) without changes in the amplitude of MEPPs, indicating a presynaptic effect. Pre-treatment with HCY for 2 h only slightly affected both amplitude and frequency of MEPPs but increased the inhibitory potency of H2O2 almost two fold. As HCY can activate certain subtypes of glutamate N-methyl D-aspartate (NMDA) receptors we tested the role of NMDA receptors in the sensitizing action of HCY. Remarkably, the selective blocker of NMDA receptors, AP-5 completely removed the sensitizing effect of HCY on the H2O2-induced presynaptic depressant effect. Thus, at the mammalian neuromuscular junction HCY largely increases the inhibitory effect of oxidative stress on transmitter release, via NMDA receptors activation. This combined effect of HCY and local oxidative stress can specifically contribute to the damage of presynaptic terminals in neurodegenerative motoneuron diseases, including ALS.