Qiao M, Malisza K L, Del Bigio M R, Kozlowski P, Seshia S S, Tuor U I
Institute for Biodiagnostics, National Research Council of Canada, and Departments of Pathology, University of Manitoba, Winnipeg, Manitoba, Canada.
Epilepsia. 2000 Jun;41(6):655-65. doi: 10.1111/j.1528-1157.2000.tb00225.x.
To determine whether the neuropathologic changes produced by vigabatrin (VGB; gamma-vinyl GABA) administration in the developing rat brain are reversible.
We injected rats daily with VGB (25-40 mg/kg/day, s.c.) from age 12 days for 2 weeks followed by 2 weeks of a drug-free period. Behavioral testing, magnetic resonance (MR) imaging, biochemical assays, and histologic technique were used to assess the adverse effect of VGB in developing brain and its reversibility.
At the end of 2 weeks' VGB administration: (a) there was a hyperactivity and a shortened latency to escape out of cool water; (b) white matter appeared hyperintense in T2 and diffusion-weighted MR images with 4-15% increases in T2; (c) microvacuolation, TUNEL-positive nuclei, and swollen axons were observed in the corpus callosum; (d) myelin staining indicated a reduction in myelination, as did the reduction in activities of myelin and oligodendrocyte-associated enzymes and the decrease in myelin basic protein on Western blots. Two weeks after stopping VGB administration: (a) MR images were normal, and microvacuolation was no longer in the white matter; (b) reduction in myelination reversed partially; (c) the T2 relaxation time remained elevated in the hypothalamus; and (d) the behavioral response remained abnormal.
Long-term VGB administration to young rats causes brain injury, which recovers partially on its cessation. The observed cell death, disrupted myelination, and alterations in behavior indicate a need for further safety assessment in infants and children.
确定在发育中的大鼠脑内给予氨己烯酸（VGB；γ-乙烯基γ-氨基丁酸）所产生的神经病理变化是否可逆。
从12日龄起，我们每天给大鼠皮下注射VGB（25 - 40毫克/千克/天），持续2周，随后为2周的停药期。采用行为测试、磁共振（MR）成像、生化分析和组织学技术来评估VGB对发育中脑的不良影响及其可逆性。
在给予VGB 2周结束时：（a）出现多动，从冷水中逃出的潜伏期缩短；（b）在T2加权和扩散加权MR图像中，白质呈高信号，T2值增加4 - 15%；（c）在胼胝体中观察到微空泡形成、TUNEL阳性核以及轴突肿胀；（d）髓鞘染色显示髓鞘形成减少，髓鞘和少突胶质细胞相关酶的活性降低以及Western印迹中髓鞘碱性蛋白减少也表明了这一点。停止给予VGB 2周后：（a）MR图像正常，白质中不再有微空泡形成；（b）髓鞘形成减少部分逆转；（c）下丘脑的T2弛豫时间仍然升高；（d）行为反应仍然异常。
对幼鼠长期给予VGB会导致脑损伤，停药后部分恢复。观察到的细胞死亡、髓鞘形成破坏和行为改变表明需要对婴儿和儿童进行进一步的安全性评估。
