doi:10.1016/j.freeradbiomed.2005.01.014 
Copyright © 2005 Elsevier Inc. All rights reserved.
Original Contribution
Therapeutic use of quercetin in the control of infection and anemia associated with visceral leishmaniasis
aDepartment of Physiology, Indian Institute of Chemical Biology, 4, Raja S.C. Mullick Road, Kolkata 700032, India
bMedicinal Chemistry Division, Indian Institute of Chemical Biology, 4, Raja S.C. Mullick Road, Kolkata 700032, India
Received 24 June 2004;
revised 29 October 2004;
accepted 19 January 2005.
Available online 10 February 2005.
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Abstract
Flavonoids are a broad class of plant phenolics that are known to possess a well-established protective effect against membrane lipoperoxidative damages. Oxidative damage of erythrocytes has been implicated in the reduced survival of erythrocytes during leishmanial infection. This study reveals the efficacy of five naturally occurring flavonoids in arresting the development of anemia during the postinfection period. Among the compounds studied, quercetin was most successful in inhibiting the oxidation of proteins and lipids on the red cell membranes of infected animals. Apart from its antianemic property, quercetin also seemed to be highly potent in lowering the parasite load in the spleen. Combination therapy of quercetin with the antileishmanial drug stibanate produced a better decay of 
OH in the erythrocytes of the infected animals compared to that induced by quercetin or drug treatment alone. Similar results were obtained in successful prevention of proteolytic degradation resulting in an aversion to early lysis of red cells after simultaneous treatment with quercetin and stibanate. Subsequent studies demonstrated the therapeutic efficacy of the combination treatment in the abatement of both anemia and parasitemia under the diseased condition.
Keywords: Flavonoids; Visceral leishmaniasis; Erythrocyte; Oxidative damage; Anemia; Free radicals
Fig. 1. Chemical structure of the flavonoids.
Fig. 2. Inhibitory effects of flavonoids on the oxidation of (a) membrane lipids and (b) membrane proteins in the erythrocytes of hamsters infected with L. donovani. Columns A and B represent oxidation in the control and infected group, respectively, without drug treatment. Infected animals were treated with (column C) hesperidin (30 mg/kg body wt), (D) diosmin (30 mg/kg body wt), (E) flavone A (20 mg/kg body wt), (F) rutin (40 mg/kg body wt), and (G) quercetin (10 mg/kg body wt). Details of the course of treatment are given underMaterials and methods. Nine animals were taken in each group and the results shown are the means ± SD of four separate determinations.
Fig. 3. Protective effects of flavonoids on the decrease of TRAP in hamsters infected with L. donovani. (Column A) Control (noninfected), (B) infected (without drug treatment). Infected groups were treated with (column C) hesperidin and (D) diosmin at the dose 30 mg/kg body wt each. Other infected groups were given (E) flavone A (20 mg/kg body wt), (F) rutin (40 mg/kg body wt), and (G) quercetin (10 mg/kg body wt). Results shown are means ± SD of four separate determinations. Eight animals were taken in each group under observation.
Fig. 4. Inhibition of ROS production in the erythrocytes of L. donovani-infected hamsters after treatment with quercetin and SAG. (Column A) Control (noninfected), (B) infected (without drug treatment). Infected groups were treated with (column C) quercetin, (D) SAG, and (E) a combination of quercetin and SAG. Treatment schedule is given underMaterials and methods. Percentage reductions in O2− production in the drug-treated groups with respect to column B are shown in parentheses. Six animals were taken in each group and the results are means ± SD of four separate experiments.
Fig. 5. Effects of treatment with quercetin and SAG on the (a) survival and (b) osmotic fragility of erythrocytes in hamsters infected with L. donovani. Results are means ± SD of four independent experiments and six animals were taken in each group. (Column A) Control (noninfected), (B) infected (without drug treatment), (C) infected + quercetin, (D) infected + SAG, and (E) infected + quercetin + SAG. Life span was measured using 51Cr and osmotic fragility was assessed from the lysis in 0.45% (w/v) NaCl as denoted underMaterials and methods. *p < 0.01, **p < 0.02, and ***p < 0.05 compared to (B).
Fig. 6. Therapeutic effects of treatment with quercetin, SAG, and a combination of quercetin + SAG on the (a) splenic parasite load and (b) Hb level in erythrocytes of hamsters infected with L. donovani. Values obtained in the control and experimental groups of animals (six in each group) are presented as means ± SD of four independent experiments. Percentage reductions in parasite load in the drug-treated groups with respect to infected group (without drug treatment) are given in parentheses. *p < 0.01 and **p < 0.02 compared to infected group (without drug treatment).
Fig. 7. Correction of hypoalbuminia after treatment with quercetin and SAG in hamsters during leishmanial infection. Serum albumin levels in the control (noninfected) and infected (without drug treatment) groups are shown in columns A and B, respectively. Drug treatment groups are shown as (column C) infection + quercetin, (D) infected + SAG, and (E) infected + quercetin + SAG. Six animals were taken in each group and values are means ± SD of four separate experiments. *p < 0.01 and **p < 0.02 in comparison to infected group (without drug treatment).
Table 1.
Effects of flavonoids on the development of anemia in hamsters infected with L. donovani
Details of the course of drug treatment are given underMaterials and methods. Results in the infected groups (with and without drug treatment) represent the values obtained after 2 months of infection. Nine animals were taken in each group and the data shown are the means ± SD of four independent experiments.
Table 2.
Antianemic and antileishmanial properties of flavonoids
Eight animals were taken in each group under observation and values are means ± SD of four separate determinations. Drug treatment schedule was as described underMaterials and methods. Results are from one time course after 2 months of infection (with and without drug treatment).
*p < 0.02 and **p < 0.05 compared to infected group (without drug treatment).
Table 3.
Degradation of bands 3 and 4.1 in the erythrocyte membrane of L. donovani-infected hamsters after treatment with quercetin and SAG
The intensity of band proteins on the SDS–PAGE was determined from densitometric scan, and their intensities (%) remaining after degradation were calculated taking the control level as 100%. Values shown are representative results of four independent experiments.
*p < 0.01 and **p < 0.05 in comparison to the infected group (without drug treatment).
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