Response of lead-induced oxidative stress and alterations in biogenic amines in different rat brain regions to combined administration of DMSA and MiADMSA.
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.
Flora
S J S
SJ
Division of Pharmacology and Toxicology, Defence Research and Development Establishment, Jhansi Road, Gwalior 474002, India. sjsflora@hotmail.com
Saxena
Geetu
G
Gautam
Pratibha
P
Kaur
Pushpinder
P
Gill
Kiran Dip
KD
D000588:Amines / Q000737:chemistry / Q000378:metabolism*; D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000378:metabolism*; D003300:Copper / Q000378:metabolism; D004912:Erythrocytes / Q000187:drug effects; D006418:Heme / Q000096:biosynthesis; D007854:Lead / Q000378:metabolism / Q000494:pharmacology*; D008297:Male; D018384:Oxidative Stress / Q000187:drug effects*; D051381:Rats; D017208:Rats, Wistar; D004113:Succimer / Q000008:administration & dosage* / Q000031:analogs & derivatives*; D015032:Zinc / Q000378:metabolism
D000588:Amines; D007854:Lead; D006418:Heme; D003300:Copper; D004113:Succimer; D015032:Zinc