Neurochemistry Department, National Institute of Neurology and Neurosurgery "Manuel Velasco Suárez", Av. Insurgentes Sur # 3877, Col. La Fama, Del. Tlalpan, Mexico City, C.P. 14269, Mexico.
Neurosci Lett. 2012 Oct 18;528(1):1-5. doi: 10.1016/j.neulet.2012.08.050. Epub 2012 Sep 5.
The bacteriostatic agent 4,4'-diaminodiphenylsulfone or dapsone (DDS) and some of its N,N'-dialkylated analogs have shown anticonvulsant and neuroprotective properties in different experimental models. In this study, we tested the ability of five DDS analogs (N,N'-dimethyldapsone, N,N'-diethyldapsone, N,N'-dipropyldapsone, N,N'-dibutyldapsone and N,N'-ditosyldapsone) to attenuate quinolinic acid-induced toxicity in vivo. Male Wistar rats were treated with either DDS or analogs (12.5mg/kg and equimolar doses respectively) 30 min before quinolinic acid intrastriatal stereotaxic injection (240 nmol/μl). Six days after injury, circling behavior was evaluated by counting ipsilateral turns for 1h after apomorphine challenge (1mg/kg, sc). Twenty-four hours later, rats were sacrificed and their corpora striata were dissected out to determine GABA content. Hemotoxicity of the analogs was assessed as the ability to produce methemoglobin (MHb) in vivo. Blood was sampled from tail vein within 18 h after drugs administration. Methemoglobin levels were determined by visible spectrophotometry and mean profiles of MHb-percentage versus time were obtained. All of the analogs tested decreased the number of ipsilateral turns/hour, reducing up to 67% the turns counting (p<0.05) when compared to those induced in animals receiving quinolinic acid with no treatment. N,N'-dimethylated, N,N'-diethylated and N,N'-dibutylated analogs significantly prevented the decrease of intrastriatal GABA content (p<0.05). Methemoglobin produced by the administration of analogs was significantly lower than the levels of the group receiving dapsone (p<0.05). The neuroprotective effect of analogs and their diminished hemotoxicity make them potential candidates for therapeutic applications.
抑菌剂 4,4'-二氨基二苯砜或氨苯砜（DDS）及其一些 N,N'-二烷基类似物在不同的实验模型中表现出抗惊厥和神经保护作用。在这项研究中，我们测试了五种 DDS 类似物（N,N'-二甲氨苯砜、N,N'-二乙氨苯砜、N,N'-二丙氨苯砜、N,N'-二丁氨苯砜和 N,N'-二对甲苯磺酰氨苯砜）在体内减轻喹啉酸诱导的毒性的能力。雄性 Wistar 大鼠在喹啉酸立体定向纹状体内注射（240nmol/μl）前 30 分钟分别用 DDS 或类似物（12.5mg/kg 和等摩尔剂量）处理。损伤后 6 天，通过阿扑吗啡（1mg/kg，sc）挑战后 1 小时内计算同侧旋转次数来评估旋转行为。24 小时后，处死大鼠，取出其纹状体以确定 GABA 含量。类似物的血液毒性通过体内产生高铁血红蛋白（MHb）的能力来评估。在药物给药后 18 小时内从尾静脉采血。通过可见分光光度法测定高铁血红蛋白水平，并获得 MHb-百分比与时间的平均曲线。所有测试的类似物均减少了同侧旋转次数/小时，与未接受治疗的接受喹啉酸的动物相比，减少了高达 67%的旋转次数（p<0.05）。N,N'-二甲基化、N,N'-二乙基化和 N,N'-二丁基化类似物显著防止了纹状体 GABA 含量的降低（p<0.05）。与接受 DDS 的组相比，类似物给药产生的高铁血红蛋白明显较低（p<0.05）。类似物的神经保护作用及其降低的血液毒性使它们成为治疗应用的潜在候选药物。
