Flora S J S, Saxena Geetu, Gautam Pratibha, Kaur Pushpinder, Gill Kiran Dip
Division of Pharmacology and Toxicology, Defence Research and Development Establishment, Jhansi Road, Gwalior 474002, India.
Chem Biol Interact. 2007 Dec 15;170(3):209-20. doi: 10.1016/j.cbi.2007.08.003. Epub 2007 Aug 12.
The present study was planned to investigate if combined administration of meso-2,3-dimercaptosuccinic acid (DMSA) and monoisoamyl DMSA (MiADMSA) could achieve better recovery in the altered biochemical parameters suggestive of brain oxidative stress and depletion of lead from blood and brain following acute lead exposure. Male Wistar rats were exposed to lead nitrate (50 mg/kg, i.p., once daily for 5 days) followed by treatment with the above chelating agents using two different doses of 25 or 50 mg/kg (orally) either alone and in combination once daily for five consecutive days. Lead exposure resulted in the significant inhibition of delta-aminolevulinic acid dehydratase activity and depletion of glutathione (GSH) in blood. These changes were accompanied by significant reduction in blood hemoglobin, RBC levels and superoxide dismutase and catalase activities. Significant increase in blood reactive oxygen species (ROS) and thiobarbituric acid reactive substances (TBARS) levels were noted. We observed marked increase in brain ROS level while GSH/oxidized glutathione ratio showed significant decrease accompanied by a significant increase in blood and brain lead concentration. The levels of norepinephrine, dopamine and serotonin in different brain regions were also altered on lead exposure. Co-administration of DMSA and MiADMSA particularly at the lower dose was most effective in the recovery of lead-induced changes in the hematological variables and oxidative stress and resulted in more pronounced depletion of lead from blood and brain compared to monotherapy with these chelators. On the other hand, combined administration of MiADMSA (50 mg/kg) in combination with DMSA (25 mg/kg each) had additional beneficial effect over the individual effect of chelating agent in the recovery of altered levels of brain biogenic amines. The study suggests that administration of MiADMSA is generally a better lead chelator than DMSA while combined administration of DMSA and MiADMSA might be a better treatment option compared to monotherapy at least in the removal of lead from the target tissues.
本研究旨在调查中-2,3-二巯基丁二酸（DMSA）和单异戊基DMSA（MiADMSA）联合给药是否能使急性铅暴露后提示脑氧化应激的生化参数改变以及血液和脑中铅的清除得到更好的恢复。雄性Wistar大鼠暴露于硝酸铅（50mg/kg，腹腔注射，每日一次，共5天），随后用上述螯合剂进行治疗，单独或联合使用两种不同剂量（25或50mg/kg，口服），每日一次，连续5天。铅暴露导致血液中δ-氨基乙酰丙酸脱水酶活性显著抑制和谷胱甘肽（GSH）耗竭。这些变化伴随着血液血红蛋白、红细胞水平以及超氧化物歧化酶和过氧化氢酶活性的显著降低。血液中活性氧（ROS）和硫代巴比妥酸反应性物质（TBARS）水平显著升高。我们观察到脑ROS水平显著升高，而GSH/氧化型谷胱甘肽比值显著降低，同时血液和脑中铅浓度显著升高。铅暴露还改变了不同脑区去甲肾上腺素、多巴胺和5-羟色胺的水平。DMSA和MiADMSA联合给药，尤其是低剂量时，对铅诱导的血液学变量变化和氧化应激恢复最为有效，与这些螯合剂单一疗法相比，能使血液和脑中的铅更显著地清除。另一方面，MiADMSA（50mg/kg）与DMSA（各25mg/kg）联合给药在恢复脑生物胺水平改变方面比螯合剂的单一作用具有额外的有益效果。该研究表明，一般而言，MiADMSA作为铅螯合剂比DMSA更好，而DMSA和MiADMSA联合给药与单一疗法相比可能是更好的治疗选择，至少在从靶组织中清除铅方面是如此。
