A bout analysis reveals age-related methylmercury neurotoxicity and nimodipine neuroprotection.
A bout analysis reveals age-related methylmercury neurotoxicity and nimodipine neuroprotection.
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一项分析揭示了与年龄相关的甲基汞神经毒性和尼莫地平神经保护作用。
DOI：
10.1016/j.bbr.2016.05.032
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发表时间：
2016
影响因子：
2.7
通讯作者：
Newland,MChristopher
中科院分区：
文献类型：
--
作者：
Shen,AndrewNathanael;Cummings,Craig;Pope,Derek;Hoffman,Daniel;Newland,MChristopher
运动和认知功能中与甲基汞相关的缺陷可能是由神经末梢中钙（Ca 2+）稳态的扰动引起的，这种机制也被认为是介导甲基汞（MeHg）神经毒性的机制。钙通道阻滞剂（CCBs）保护成年小鼠免受甲基汞毒性，但对其他年龄组的疗效知之甚少。将两个年龄组的BALB/c小鼠暴露于0或1.2 mg/kg/天的甲基汞和0或20 mg/kg/天的CCB尼莫地平，持续约8.5个月。成年犬在出生后第72天开始接触，退休饲养员在出生后第296天开始接触。高速率操作性行为保持在百分位时间表下，这有助于将应答率与应答率分离。使用对数幸存者回合分析方法分析反应，该方法将行为划分为由停顿分隔的高频率回合。甲基汞诱导的死亡率并不依赖于年龄，但尼莫地平的神经保护是年龄依赖性的，与较差的保护发生在老年小鼠。内回合反应率（感觉运动功能的标志）是更敏感的甲基汞毒性比回合启动率（动机的标志）。在仅使用甲基汞的退休饲养员出现明显毒性体征前近2个月内，饲养场内发生率下降，但成年饲养员未出现，表明年幼动物的毒性延迟更大。在相对健康的成年甲基汞+ NIM动物中也出现了基于电机的递减。衰老似乎改变了Ca 2+稳态的基础过程，从而减少尼莫地平的保护作用，即使在没有达到衰老的小鼠中也是如此。对甲基汞接触的研究提供了一个实验模型，可用于研究潜在的衰老机制。
Age-related deficits in motor and cognitive functioning may be driven by perturbations in calcium (Ca2+) homeostasis in nerve terminals, mechanisms that are also thought to mediate the neurotoxicity of methylmercury (MeHg). Calcium-channel blockers (CCBs) protect against MeHg toxicity in adult mice, but little is known about their efficacy in other age groups. Two age groups of BALB/c mice were exposed to 0 or 1.2 mg/kg/day MeHg and 0 or 20 mg/kg/day of the CCB nimodipine for approximately 8.5 months. Adults began exposure on postnatal day (PND) 72 and the retired breeders on PND 296. High-rate operant behavior was maintained under a percentile schedule, which helped to decouple response rate from reinforcer rate. Responding was analyzed using a log-survivor bout analysis approach that partitioned behavior into high-rate bouts separated by pauses. MeHg-induced mortality did not depend on age but nimodipine neuroprotection was age-dependent, with poorer protection occurring in older mice. Within-bout response rate (a marker of sensorimotor function) was more sensitive to MeHg toxicity than bout-initiation rate (a marker of motivation). Within-bout rate declined almost 2 months prior to overt signs of toxicity for the MeHg-only retired breeders but not adults, suggesting greater delay to toxicity in younger animals. Motor-based decrements also appeared in relatively healthy adult MeHg + NIM animals. Aging appeared to alter the processes underlying Ca2+homeostasis thereby diminishing protection by nimodipine, even in mice that have not reached senescence. The study of MeHg exposure presents an experimental model by which to study potential mechanisms of aging.