Nishino H, Kumazaki M, Fukuda A, Fujimoto I, Shimano Y, Hida H, Sakurai T, Deshpande S B, Shimizu H, Morikawa S, Inubushi T
Department of Physiology, Nagoya City University Medical School, Mizuho-ku, Nagoya, Japan.
Neurosci Res. 1997 Apr;27(4):343-55. doi: 10.1016/s0168-0102(97)01170-x.
Mechanisms underlying the selective vulnerability of the lateral striatal area to the toxic effects of 3-nitropropionic acid (3-NPA) were investigated in rats. A single exposure to 3-NPA (20 mg/kg, s.c.) induced no deficits in behavior and histology, but subsequent injection produced motor symptoms, catalepsy, lip smacking, abnormal gait, paddling, rolling, opisthotonos, tremor, recombence, somnolence and so on, in 30% of the animals within a few hours. Diffusion-weighted magnetic resonance imaging of the brains revealed an area of high signal intensity in the bilateral striata. By this stage (within a few hours), striatal astrocytes had become swollen and disintegrated. Extravasation of immunoglobulin G was detected, indicating blood-brain barrier (BBB) dysfunction. Electron microscopy revealed edema and disorganization of structures inside the astrocytic end-feet around the branches of the lateral striatal artery. Neurons were less vulnerable than astrocytes to the 3-NPA injury. Treatment of the rats with D2 receptor agonist prior to exposure to 3-NPA attenuated the behavioral abnormalities and histological damage whereas pretreatment with D2 antagonist exacerbated these changes. The concentrations of extracellular dopamine (DA) and dihydroxyphenyl acetic acid (DOPAC) were both increased in rats exposed to 3-NPA. In vitro imaging of astrocytes revealed a progressive increase in [Ca2+]i after superfusion with 3-NPA, and the 'ceiling' level was maintained even after extensive washing. DA superfusion also increased the astrocytic [Ca2+]i and this increase was reversible. Data indicate that 3-NPA-induced striatal damage was associated with astrocytic cell death and dysfunction of the BBB. Intracellular edema and extreme Ca2+ overload induced by the toxin were further aggravated by an increase in the level of DA activity. These factors acting either singly or in combination may trigger astrocyte destruction.
在大鼠中研究了外侧纹状体区域对3-硝基丙酸（3-NPA）毒性作用选择性易损性的潜在机制。单次皮下注射3-NPA（20mg/kg）未引起行为和组织学缺陷，但随后注射在数小时内使30%的动物出现运动症状、僵住、咂嘴、异常步态、划水、翻滚、角弓反张、震颤、共济失调、嗜睡等。大脑的扩散加权磁共振成像显示双侧纹状体有高信号强度区域。在此阶段（数小时内），纹状体星形胶质细胞已肿胀并解体。检测到免疫球蛋白G外渗，表明血脑屏障（BBB）功能障碍。电子显微镜显示外侧纹状体动脉分支周围星形胶质细胞终足内结构水肿和紊乱。神经元比星形胶质细胞对3-NPA损伤更不易感。在暴露于3-NPA之前用D2受体激动剂治疗大鼠可减轻行为异常和组织学损伤，而用D2拮抗剂预处理则会加剧这些变化。暴露于3-NPA的大鼠细胞外多巴胺（DA）和二羟基苯乙酸（DOPAC）浓度均升高。星形胶质细胞的体外成像显示用3-NPA灌注后[Ca2+]i逐渐增加，即使经过大量冲洗，“峰值”水平仍保持不变。DA灌注也增加了星形胶质细胞的[Ca2+]i，且这种增加是可逆的。数据表明3-NPA诱导的纹状体损伤与星形胶质细胞死亡和血脑屏障功能障碍有关。毒素诱导的细胞内水肿和极端Ca2+超载因DA活性水平升高而进一步加重。这些因素单独或共同作用可能触发星形胶质细胞破坏。
