Lead induced oxidative damage and its response to combined administration of alpha-lipoic acid and succimers in rats.
Alpha-lipoic acid (LA) has been reported to be highly effective in improving the thiol capacity of the cells and in reducing lead induced oxidative stress. These results suggested its possible role as a therapeutic intervention of lead poisoning in combination with a chelator. We investigated the effects of LA, either alone or when administered in combination with succimer (meso 2,3-dimercaptosuccinic acid; DMSA or one of its analogue monoisoamyl DMSA), in influencing the lead induced alterations in haem synthesis pathway, hepatic, renal and brain oxidative stress and lead concentration from blood and soft tissues. The results suggest a significant lead induced inhibition of delta-aminolevulinic acid dehydratase (ALAD), reduction in glutathione (GSH) and an increased zinc protoporphyrin (ZPP) level in blood, indicating altered heme synthesis pathway. Both the thiol chelators were able to increase blood ALAD activity and GSH level towards normal. The most prominent effect on blood ALAD activity was however observed when monoisoamyl DMSA (MiADMSA) was co-administered with LA. Lead exposure produced significant depletion of hepatic GSH, while, oxidized glutahione (GSSG), thiobarbituric acid reactive substances (TBARS) and catalase activity increased significantly, suggesting hepatic oxidative stress. All the treatments were able to increase hepatic GSH and reduce GSSG levels, while, TBARS level reduced significantly in animals administered LA and MiADMSA, individually or in combination. Lead induced increase in renal GSSG, TBARS levels and catalase activity, were effectively reduced by LA, while, the two chelators when administered alone were effective only in reducing GSSG and catalase activity. The most prominent beneficial effects, however, were observed in animals treated concomitantly with LA and one of the chelators (DMSA or MiADMSA). Brain GSH and GSSG levels decreased moderately while superoxide dismutase (SOD) activity remained statistically unaltered on lead exposure. Brain catalase activity, on the other hand, increased significantly. Administration of LA was effective in reducing these alterations in the brain, however, the best effects were achieved in animals co-administered LA and one of the thiol chelators. The results point to a significant beneficial role of LA in the recovery of altered biochemical variables both during monotherapy and when given in combination with succimer. It however, showed no chelating properties in decreasing lead burden from blood, liver and kidneys except for a significantly more pronounced decrease in brain lead concentration in animals administered LA plus thiol chelators, compared to the effects of chelating agents alone. This is an interesting and notable observation, which requires further exploration. The results thus provide evidence of an encouraging role of LA when given in combination with a thiol chelator in the therapeutic intervention of lead poisoning, particularly in reducing the oxidative stress and brain lead concentration.
Division of Pharmacology and Toxicology, Defence Research and Development Establishment, Jhansi Road, Gwalior, India.
Manisha
M
Pande
S J S
SJ
Flora
D000818:Animals; D000975:Antioxidants / Q000008:administration & dosage*; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D002614:Chelating Agents / Q000008:administration & dosage*; D004359:Drug Therapy, Combination; D005978:Glutathione / Q000378:metabolism; D006410:Hematopoiesis / Q000187:drug effects; D007668:Kidney / Q000187:drug effects / Q000378:metabolism; D007854:Lead / Q000378:metabolism / Q000633:toxicity*; D008297:Male; D018384:Oxidative Stress; D051381:Rats; D017208:Rats, Wistar; D004113:Succimer / Q000008:administration & dosage*; D013482:Superoxide Dismutase / Q000378:metabolism; D008063:Thioctic Acid / Q000008:administration & dosage*
D000975:Antioxidants; D002614:Chelating Agents; D007854:Lead; D008063:Thioctic Acid; D004113:Succimer; D013482:Superoxide Dismutase; D005978:Glutathione