Combinational chelation therapy abrogates lead-induced neurodegeneration in rats.
Lead, a ubiquitous and potent neurotoxicant causes oxidative stress which leads to numerous neurobehavioral and physiological alterations. The ability of lead to bind sulfhydryl groups or compete with calcium could be one of the reasons for its debilitating effects. In the present study, we addressed: i) if chelation therapy could circumvent the altered oxidative stress and prevent neuronal apoptosis in chronic lead-intoxicated rats, ii) whether chelation therapy could reverse biochemical and behavioral changes, and iii) if mono or combinational therapy with captopril (an antioxidant) and thiol chelating agents (DMSA/MiADMSA) is more effective than individual thiol chelator in lead-exposed rats. Results indicated that lead caused a significant increase in reactive oxygen species, nitric oxide, and intracellular free calcium levels along with altered behavioral abnormalities in locomotor activity, exploratory behavior, learning, and memory that were supported by changes in neurotransmitter levels. A fall in membrane potential, release of cytochrome c, and DNA damage indicated mitochondrial-dependent apoptosis. Most of these alterations showed significant recovery following combined therapy with captopril with MiADMSA and to a smaller extend with captopril+DMSA over monotherapy with these chelators. It could be concluded from our present results that co-administration of a potent antioxidant (like captopril) might be a better treatment protocol than monotherapy to counter lead-induced oxidative stress. The major highlight of the work is an interesting experimental evidence of the efficacy of combinational therapy using an antioxidant with a thiol chelator in reversing neurological dystrophy caused due to chronic lead exposure in rats.
Pachauri
Vidhu
V
Division of Pharmacology and Toxicology, Defence Research and Development Establishment, Jhansi Road, Gwalior-474 001, India.
Saxena
Geetu
G
Mehta
Ashish
A
Mishra
Deepshikha
D
Flora
Swaran J S
SJ
D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001522:Behavior, Animal / Q000187:drug effects; D001679:Biogenic Amines / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D002216:Captopril / Q000494:pharmacology*; D002614:Chelating Agents / Q000494:pharmacology*; D045304:Cytochromes c / Q000378:metabolism; D004249:DNA Damage; D004195:Disease Models, Animal; D004359:Drug Therapy, Combination; D005106:Exploratory Behavior / Q000187:drug effects; D020263:Lead Poisoning, Nervous System / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D007858:Learning / Q000187:drug effects; D008297:Male; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008568:Memory / Q000187:drug effects; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D009043:Motor Activity / Q000187:drug effects; D009410:Nerve Degeneration / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D009569:Nitric Oxide / Q000378:metabolism; D009942:Organometallic Compounds; D018384:Oxidative Stress / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar; D017382:Reactive Oxygen Species / Q000378:metabolism; D004113:Succimer / Q000031:analogs & derivatives* / Q000494:pharmacology
D000975:Antioxidants; D001679:Biogenic Amines; D002614:Chelating Agents; D009942:Organometallic Compounds; D017382:Reactive Oxygen Species; D009569:Nitric Oxide; D045304:Cytochromes c; D002216:Captopril; C091888:monoisoamyl-2,3-dimercaptosuccinate; D004113:Succimer; C008261:lead acetate; D002118:Calcium