title: Lead induced oxidative stress and its recovery following co-administration of melatonin or N-acetylcysteine during chelation with succimer in male rats.
abstract: Lead is a ubiquitous element in the environment causing oxidative burst in the exposed individuals leading to tissue damage. Antioxidants have long been known to reduce the free radical-mediated oxidative stress while, thiol chelators have been used to treat arsenic toxicity. The therapeutic efficacy of melatonin or N-acetylcysteine (NAC) was studied in the present study, both individually and in combination with a potent thiol-chelating agent, meso 2,3-dimercaptosuccinic acid (DMSA), in reducing lead concentration in blood and other soft tissues. Their ability to restore altered haematopoietic, hepatic and other biochemical variables indicative of tissue oxidative stress in male rats was also investigated. Administration of melatonin and NAC individually, provided significant protection to lead induced disturbed antioxidant defense that may significantly compromise normal cellular function. Administration of melatonin and NAC also provided a significant protection to thiobarbituric acid reactive substances (TBARS) levels, reduced glutathione (GSH) and oxidized glutathione (GSSG) contents in tissues, suggesting their ability to act as a free radical scavenger and in protecting cells against toxic insult. NAC, a thiol containing antioxidant, has been used under several clinical conditions with few adverse side effects. It has a high toxicity threshold and its wide therapeutic window enhances its utility. The antioxidant action of NAC is due to its ability to interact with reactive oxygen species (ROS) or its ability to stimulate endogenous glutathione (GSH) synthesis. DMSA, on the other hand when given alone, provided significant recovery in restoring the altered lead sensitive biochemical indices like blood delta-aminolevulinic acid dehydratase (ALAD), urinary delta-aminolevulinic acid (ALA), beside increasing urinary lead excretion and decreasing lead concentration in blood and soft tissues. Interestingly, combined treatment of DMSA and NAC provided more pronounced efficacy in restoring altered biochemical variables and in reducing body lead burden than monotherapy with DMSA. The results thus, suggest the involvement of ROS in lead toxicity and a pronounced beneficial role of NAC in therapeutic implications of lead poisoning when co-administered with a thiol chelator (DMSA) supporting the hypothesis that cellular redox status may be significantly reversed by utilizing a thiol containing antioxidant compound. It can be concluded that, combined therapy with an antioxidant moiety and a thiol-chelating agent may be a better choice for treating plumbism.
authors.affiliation: Defence Research and Development Establishment, Gwalior 474 002, India. sjsflora@hotmail.com
authors.forename: S J S
authors.initials: SJ
authors.lastname: Flora
authors.forename: M
authors.initials: M
authors.lastname: Pande
authors.forename: G M
authors.initials: GM
authors.lastname: Kannan
authors.forename: A
authors.initials: A
authors.lastname: Mehta
mesh_terms: D000111:Acetylcysteine / Q000008:administration & dosage / Q000627:therapeutic use*; D000818:Animals; D000975:Antioxidants / Q000627:therapeutic use*; D001921:Brain / Q000187:drug effects; D001923:Brain Chemistry; D002614:Chelating Agents / Q000627:therapeutic use*; D007668:Kidney / Q000737:chemistry / Q000187:drug effects; D007854:Lead / Q000032:analysis; D007855:Lead Poisoning / Q000201:enzymology / Q000378:metabolism / Q000517:prevention & control*; D008099:Liver / Q000737:chemistry / Q000187:drug effects; D008297:Male; D008550:Melatonin / Q000008:administration & dosage / Q000627:therapeutic use*; D018384:Oxidative Stress / Q000187:drug effects*; D051381:Rats; D004113:Succimer / Q000627:therapeutic use*
chemical_list: D000975:Antioxidants; D002614:Chelating Agents; D007854:Lead; D004113:Succimer; D008550:Melatonin; D000111:Acetylcysteine