Gurusamy M. Kannan

Concomitant administration of Moringa oleifera seed powder in the remediation of arsenic-induced oxidative stress in mouse

Contamination of ground water by arsenic has become a cause of global public health concern. In West Bengal, India, almost 6 million people are endemically exposed to inorganic arsenic by drinking heavily contaminated groundwater through hand‐pumped tube wells. No safe, effective and specific preventive or therapeutic measures for treating arsenic poisoning are available. We recently reported that some of the herbal extracts possess properties effective in reducing arsenic concentration and in restoring some of the toxic effects of arsenic in animal models. Moringa oleifera Lamarack (English: Horseradish‐tree, Drumstick‐tree, Hindi: Saijan, Sanskrit: Shigru) belongs to the Moringaceae family, is generally known in the developing world as a vegetable, a medicinal plant and a source of vegetable oil.

Toxic effects of arsenic (III) on some hematopoietic and central nervous system variables in rats and guinea pigs.

Objective: To evaluate the effects of arsenic (III) exposure on porphyrin metabolism and the central nervous system supplemented with data on the effect of hepatic and renal tissues of rats and guinea pigs. Methods: Rats and guinea pigs were exposed to 10 or 25 ppm arsenic in drinking water for 16 weeks. Results: Following chronic arsenic (III) exposure, δ-aminolevulinic acid dehydratase activity in blood showed a significant reduction as did the total cell counts (RBC and WBC) and reduced glutathione with increased urinary δ-aminolevulinic acid. Zinc protoporphyrin, a sensitive indicator of iron deficiency and impairment of heme biosynthesis, showed a significant increase in arsenic exposure. The hepatic δ-aminolevulinic acid dehydratase and δ-aminolevulinic acid synthetase activity increased in chronic arsenic (III) exposure in rats and guinea pigs. Significant changes in the steady-state level of three major neurotransmitters, dopamine, norepinephrine, and 5-hydroxytryptamine, and monoamine oxidase were observed following chronic arsenic (III) exposure. Conclusion: At low doses (10 and 25 ppm in drinking water), the effects of arsenic on hematopoietic indices and whole-brain neurotransmitter concentrations were more prominent in guinea pigs than in rats with some variability in the dose response.

Chronic arsenic poisoning in the rat: treatment with combined administration of succimers and an antioxidant.

The influence of the coadministration of vitamin C or vitamin E on the efficacy of two thiol chelators, meso-2,3-dimercaptosuccinic acid (DMSA) or monoisoamyl DMSA, in counteracting chronic arsenic toxicity was investigated in rats. Vitamin C and vitamin E were only mildly effective when given alone or in combination with the above chelators in mobilizing arsenic from the target tissues. However, combined administration of vitamin C plus DMSA and vitamin E plus MiADMSA led to a more pronounced depletion of brain arsenic. The supplementation of vitamins was significantly effective in restoring inhibition of blood delta-aminolevulinic acid dehydratase (ALAD) oxidative stress in liver, kidneys, and brain as reflected by reduced levels of thiobarbituric acid reactive substance and oxidized and reduced glutathione levels. The results thus lead us to suggest that coadministration of vitamin E or vitamin C may be useful in the restoration of altered biochemical variables (particularly the effects on heme biosynthesis and oxidative injury) although it has only a limited role in depleting arsenic burden.

Arsenic-induced changes in certain neurotransmitter levels and their recoveries following chelation in rat whole brain.

Arsenic as sodium arsenite (100 ppm in drinking water) was administered to male rats for 16 weeks. Animals were then treated either with meso-2,3-dimercaptosuccinic acid (DMSA), sodium 2,3-dimercaptopropane 1-sulfonate (DMPS), dimethyl DMSA (DmDMSA), or diisopropyl DMSA (DiPDMSA) twice daily (50 mg/kg) intraperitoneally for 5 days. After 5 days of rest period, the animals were again given a second course of chelation therapy. The animals were sacrificed subsequently for the determination of whole brain biogenic amines levels, acetylcholinesterase (AChE), monoamine oxidase (MAO) and delta-aminolevulinic acid dehydratase (ALAD) activities. A number of biochemical parameters and arsenic concentrations in some tissues were also determined. The results suggest a significant increase in brain arsenic concentration accompanied by alterations in neurotransmitters levels following As(III) exposure. Although chelation treatment was effective in reducing As burden, the altered biochemical variables responded less favorably to chelation therapy. The DMSA-diesters, particularly DiPDMSA, produced a more pronounced increase in brain arsenic burden, as well as alterations in a few neurotransmitters. It can be concluded that the lipophilic character of As antidotes may lead to unfavorable results following intraperitoneal administration.

Therapeutic effects of Moringa oleifera on arsenic-induced toxicity in rats.

Moringa oleifera Lamarack (English: Horseradish-tree, Drumstick-tree; Hindi: Saijan; Sanskrit: Shigru) belongs to the Moringaceae family, is generally known in the developing world as a vegetable, a medicinal plant and a source of vegetable oil. Besides, the plant is reported to have various biological activities, including hypocholesterolemic agent, regulation of thyroid hormone status, anti-diabetic agent, gastric ulcers, anti-tumor agent and hypotensive agent, used for treating various diseases such as inflammation, cardiovascular and liver diseases. Therapeutic efficacy of oral administration of seed powder of M. oleifera (500mg/kg, orally, once daily) post arsenic exposure (100ppm in drinking water for 4 months) was investigated in rats. Animals exposed to arsenic(III) showed a significant inhibition of δ-aminolevulinic acid dehydratase (ALAD) activity, decrease in reduced glutathione (GSH) level and an increase in reactive oxygen species (ROS) in blood. On the other hand, a significant decrease in hepatic ALAD, and an increase in δ-aminolevulinic acid synthetase (ALAS) activity was noted after arsenic exposure. These changes were accompanied by an increase in thiobarbiturc acid reactive substances (TBARS) level in liver and kidney. Activities of liver, kidney and brain superoxide dismutase (SOD) and catalase also showed a decrease on arsenic exposure. Administration of M. oleifera seed powder post arsenic exposure, exhibited significant recovery in blood ALAD activity while, it restored blood GSH and ROS levels. Most of the other blood biochemical variables remained unchanged on M. oleifera supplementation. A significant protection in the altered ALAD and ALAS activities of liver and TBARS level in liver and kidney was however, observed after M. oleifera administration. Interestingly, there was a marginal but significant depletion of arsenic from blood, liver and kidneys. The results, thus lead us to conclude that post arsenic exposure administration with the seed powder of M. oleifera has significant role in protecting animals from arsenic-induced oxidative stress and in the depletion of arsenic concentration. Further studies thus can be recommended for determining the effect of co-administrating seed powder of M. oleifera during chelation therapy with a thiol chelator.

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 Alzheimers 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.

Meso 2,3-dimercaptosuccinic acid (DMSA) and monoisoamyl DMSA effect on gallium arsenide induced pathological liver injury in rats

The effect of meso 2,3-dimercaptosuccinic acid (DMSA) and monoisoamyl DMSA (MiADMSA) on gallium arsenide (GaAs) induced liver damage was studied. The oral feeding rat model was used in this study. The animals were exposed to 10 mg/kg GaAs, orally, once daily, 5 days a week for 24 weeks and treated thereafter with single oral daily dose of either 0.3 mmol/kg DMSA or MiADMSA for two course of 5 days treatment. The animals were sacrificed thereafter. Lipid peroxidation was assessed by measuring liver thiobarbituric acid reactive substance (TBARS). Liver damage was assessed by number of biochemical variables and by light microscopy. The activity of superoxide dismutase (SOD) and delta-aminolevulinic acid dehydratase (ALAD) beside reduced glutathione (GSH) concentration was measured in blood. Exposure to GaAs produced a significant reduction in GSH while, increased the oxidized glutathione (GSSG) concentration. Hepatic glutathione peroxidase (GPx) and catalase activity increased significantly while level of serum transaminase increased moderately. Gallium arsenide exposure also produced marked hepatic histopathological lesions. Overall, treatment with MiADMSA proved to be better than DMSA in the mobilization of arsenic and in the turnover of some of the above mentioned GaAs sensitive biochemical alterations. Histopathological lesions also, responded more favorably to chelation treatment with MiADMSA than DMSA.

Acute oral gallium arsenide exposure and changes in certain hematological, hepatic, renal and immunological indices at different time intervals in male Wistar rats.

Male albino rats were given a single oral dose of gallium arsenide (GaAs) (100, 200 or 500 mg/kg). Erythrocyte delta-aminolevulinic acid dehydratase (ALAD) activity was inhibited in all the three GaAs-exposed groups accompanied by elevated urinary excretion of ALA. A significant increase in serum aspartate aminotransferase (AST) activity, and gamma-glutamyltranspeptidase (gamma-GT) was observed. A significant increase in hepatic malondialdehyde (MDA) and a decrease in hepatic glutathione contents were also noted. Renal alkaline phosphatase activity, urinary ALA and protein excretion increased significantly on GaAs exposure. These changes were accompanied by significant alterations in almost all the immunological variables, with an increase in gallium and arsenic concentration in blood and soft tissues. While most of the above biochemical alterations were prominent at day 7 following single exposure to 200 and 500 mg/kg GaAs, most of the immunological indices altered with all the three doses and remained high even at day 21. The results suggest only a moderate effect of GaAs on renal and hepatic tissues. By contrast, immunological and haematological systems are the most vulnerable to the toxic effects of GaAs.

Selenium effects on gallium arsenide induced biochemical and immunotoxicological changes in rats.

The influence of selenium (6.3 and 12.6 micromol/kg, intraperitoneally) on the disposition of gallium and arsenic and a few gallium arsenide (GaAs) sensitive biochemical variables was studied in male rats. Concomitant administration of Se and GaAs (70 micromol/kg, orally, 5 days a week for 4 weeks) significantly prevented the accumulation of arsenic while, the gallium concentration reduced moderately in the soft organs. The biochemical (haematopoietic and liver) and immunological variables however, responded less favorably to selenium administration. Most of the protection was however observed with the dose of 12.6 micromol rather than at 6.3 micromol. The results thus suggest a few beneficial effects of selenium in preventing the appearance of signs of GaAs toxicity like preventing inhibition of blood delta-aminolevulinic acid dehydratase (ALAD), hepatic malondialdehyde (MDA) formation and the accumulation of gallium and arsenic concentration.

Combined administration of taurine and meso 2,3-dimercaptosuccinic acid in the treatment of chronic lead intoxication in rats

The present study describes the dose–dependent effect of taurine, an amino acid and a known antioxidant, either alone or in combination with meso 2,3–dimercaptosucci–nic acid (DMSA) in the treatment of subchronic lead intoxication in male rats. The effects of these treatments in influencing the lead–induced alterations in haem synthesis, hepatic, renal or brain oxidative stress and lead concentration from soft tissues were investigated. Exposure to lead produced a significant inhibition of blood–aminolevulinic acid dehydratase (ALAD) activity, reduction in glutathione (GSH) and an increase in zinc protoporphyrin (ZPP) suggesting an altered haem synthesis pathway. Only DMSA was able to increase the activity of ALAD, while both taurine and DMSA were able to significantly increase GSH level towards normal. Animals treated with taurine significantly reduced the alterations in some of the biochemical parameters indicative of oxidative stress. Thiobarbituric acid reactive substance (TBARS) levels reduced significantly in liver, kidney and red blood cells, while GSH level increased. Activity of superoxide dismutase (SOD) also showed an increase in blood and brain in animals treated with taurine. The data also provided a promising role of taurine during chelation of lead by potentiating the depletion of blood, liver and brain lead compared to DMSA alone. It can thus be concluded from the study that concomitant administration of an antioxidant could play a significant and important role in abating a number of toxic effects of lead when administered along with the thiol chelators.