Department of Neurology, Oregon Health & Science University, Portland, OR 97239, USA.
Neurotoxicology. 2012 Jun;33(3):429-35. doi: 10.1016/j.neuro.2012.04.006. Epub 2012 Apr 15.
Previous patch-clamp studies by our laboratory showed that acute exposure to the pesticide rotenone augments inward currents evoked by N-methyl-d-aspartate (NMDA) in substantia nigra zona compacta (SNC) dopamine neurons in slices of rat brain. The present experiments were done to search for histological evidence of increased neurotoxicity produced by combined rotenone and NMDA treatments. In horizontal slices of rat midbrain, we found that a 30 min superfusion with 100 nM rotenone caused significant injury to tyrosine hydroxylase (TH)-positive proximal dendrites in dorsal and ventral regions of the SNC and ventral tegmental area (VTA). Moreover, treatment with 100 μM NMDA potentiated rotenone toxicity. In contrast, treatment with 30 μM NMDA protected against rotenone-induced injury to dendrites in the ventral SNC and ventral VTA. Interestingly, treatment with 30 μM NMDA-alone produced an apparent increase in proximal dendrite scores in ventral SNC and dorsal VTA. We conclude that NMDA has concentration-dependent actions on rotenone toxicity that differ according to regional subtype of dopamine neuron.
先前，本实验室的膜片钳研究表明，急性暴露于杀虫剂鱼藤酮会增强大鼠脑切片中黑质致密部（SNC）多巴胺神经元中 N-甲基-D-天冬氨酸（NMDA）诱发的内向电流。本实验旨在寻找由鱼藤酮和 NMDA 联合处理引起的神经毒性增加的组织学证据。在大鼠中脑的水平切片中，我们发现，用 100 nM 鱼藤酮进行 30 分钟的超滤液处理会导致 SNC 和腹侧被盖区（VTA）的背侧和腹侧区域以及腹侧中脑导水管周围灰质（VTA）中的酪氨酸羟化酶（TH）阳性近端树突受到显著损伤。此外，用 100 μM NMDA 处理会增强鱼藤酮的毒性。相比之下，用 30 μM NMDA 处理可防止 SNC 腹侧和 VTA 腹侧的树突受到鱼藤酮诱导的损伤。有趣的是，用 30 μM NMDA 单独处理会明显增加 SNC 腹侧和 VTA 背侧的近端树突评分。我们的结论是，NMDA 对鱼藤酮毒性具有浓度依赖性作用，根据多巴胺神经元的区域亚型而有所不同。
