Aluminum-induced oxidative stress in rat brain: response to combined administration of citric acid and HEDTA.
Aluminum, a known neurotoxic substance, has been suggested as a contributing factor in the pathogenesis of Alzheimer's disease. Therapeutic efficacy of combined administration of citric acid (CA) and N-(2-hydroxyethyl) ethylenediaminetriacetic acid (HEDTA) was evaluated in decreasing blood and brain aluminum concentration and parameters indicative of hematological disorders and brain oxidative stress. Adult male wistar rats were exposed to drinking water containing 0.2% aluminum nitrate for 8 months and treated once daily for 5 consecutive days with CA (50 mg/kg, orally) or HEDTA (50 mg/kg, intraperitoneally) either individually or in combination. Aluminum exposure significantly inhibited blood delta-aminolevulinic acid dehydratase while increased zinc protoporphyrin confirming changed heme biosynthesis. Significant decrease in the level of glutathione S-transferase in various brain regions and an increase in whole brain thiobarbituric acid reactive substance, and oxidized glutathione (GSSG) levels were also observed. Glutathione peroxidase activity showed a significant increase in cerebellum of aluminum exposed rats. Most of the above parameters responded moderately to the individual treatment with CA and HEDTA, but significantly reduced blood and brain aluminum burden. However, more pronounced beneficial effects on some of the above described parameters were observed when CA and HEDTA were administered concomitantly. Blood and brain aluminum concentration however, showed no further decline on combined treatment over the individual effect with HEDTA or CA. We conclude that in order to achieve an optimum effect of chelation, combined administration of CA and HEDTA might be preferred. However, further work is needed before a final recommendation could be made.
Flora
Swaran J S
SJ
Division of Pharmacology and Toxicology, Defence Research and Development Establishment, Jhansi Road, Gwalior 474002, India. sjsflora@hotmail.com
Mehta
Ashish
A
Satsangi
Kiran
K
Kannan
Gurusamy M
GM
Gupta
Manju
M
D000535:Aluminum / Q000097:blood / Q000633:toxicity*; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D002614:Chelating Agents / Q000494:pharmacology*; D019343:Citric Acid / Q000097:blood / Q000494:pharmacology*; D004357:Drug Synergism; D004492:Edetic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology*; D005978:Glutathione / Q000097:blood / Q000378:metabolism; D006418:Heme / Q000096:biosynthesis; D008297:Male; D018384:Oxidative Stress / Q000187:drug effects*; D000623:Porphobilinogen Synthase / Q000097:blood; D011524:Protoporphyrins / Q000097:blood; D051381:Rats; D017208:Rats, Wistar; D017392:Thiobarbituric Acid Reactive Substances / Q000378:metabolism
D002614:Chelating Agents; D011524:Protoporphyrins; D017392:Thiobarbituric Acid Reactive Substances; C017803:zinc protoporphyrin; D019343:Citric Acid; D006418:Heme; D004492:Edetic Acid; D000535:Aluminum; D000623:Porphobilinogen Synthase; D005978:Glutathione; C026060:N-(hydroxyethyl)ethylenediaminetriacetic acid