Table 3.
List of studies concerned with in vivo efficacy of quercetin toward different protozoan pathogens. Animal models, routes of administration, methods, dosing regimens, and key findings of the relevant studies are also outlined.
| Protozoan parasites | Identifiers | Animal models | Routes of Que administration | Methods/dosing regimens | Key findings | References |
|---|---|---|---|---|---|---|
| Leishmania amazonensis | MHOM/BR/75/Josefa | BALB/c mice | Oral (intragastric gavage) | Animals were subcutaneously infected in the ear pinna with GFP promastigotes. At 7 days p.i., animals were treated daily with Que (16 mg/kg) for 30 days | (i) Significant suppression of the parasite burden using Que compared with the untreated mice (p < 0.01) (ii) Reduction in lesion growth in mice receiving Que (iii) Superiority of Que over intraperitoneal SSG (8 mg/kg, twice a week) in reducing the parasite burden on day 68 of infection |
[72] |
| MHOM/77BR/LTB0016 | BALB/c mice | Intralesional | Animals were subcutaneously infected in the footpad with promastigotes. At 15 days p.i., they received 5 doses of Que (30 mg/kg) every 4 days | (i) Increasing values of lesion size during the first 2 weeks of treatment in Que-treated animals (ii) Significant reduction in the parasite burden (p < 0.05) at 4 and 6 weeks p.i. in Que-treated mice as compared with the untreated group (iii) Superiority of Que over Glucantime® (30 mg/kg) in reducing the parasite burden at 4 and 6 weeks p.i. (iv) No signs of animal death and no evidence of body weight loss higher than 10% in the animals exposed to Que |
[19] | |
| MHOM/BR/75/Josefa | BALB/c mice | Oral (intragastric gavage) | Animals were infected in the ear with GFP promastigotes and were given 51 daily oral doses of Que (16 mg/kg) or LNC-loaded Que (0.4 mg/kg) | (i) Reduction in the lesion sizes (38%) and parasite loads (71%) using Que (ii) Reduction in the lesion sizes (64%) and parasite loads (91%) using LNC-Que (iii) No evidence of treatment toxicity |
[73] | |
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| Leishmania braziliensis | MCAN/BR/98/R619 | Golden hamsters | Oral | Animals were infected in the dorsal hind paw with promastigotes and were treated with Que (20 mg/kg; five times a week) for 8 weeks starting on the 7th day of infection | (i) Reduction in the lesion thickness and parasite load in Que-treated hamsters as compared with the untreated group (ii) No evidence of treatment toxicity (iii) Lower in vivo efficacy of Que in comparison to 80 mg/kg of intraperitoneal Glucantime® (3 times a week, every other day) |
[28] |
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| Leishmania donovani | MHOM/IN/1983/AG83 | Golden hamsters | Oral | Animals received Que (14 mg/kg) twice a week at 4 days p.i. with freshly purified amastigotes, and the treatment was continued for 4 weeks | (i) Reduction in the splenic parasite load by 90% | [29] |
| MHOM/IN/1983/AG83 | Golden hamsters | Oral | Que (5–40 mg/kg) was administered biweekly to 1-month-infected animals | (i) Suppressing the oxidation of lipids and proteins in the RBC membranes of infected animals in response to Que treatment (ii) Rectification of anemia during infection (increasing both Hb levels and RBC lifespan) in response to Que treatment (iii) Reduction in the spleen parasite load in Que-treated animals (iv) Superiority of SSG/Que combination for reduction of •OH in RBCs, prevention of proteolytic degradation of bands 3 and 4.1 in RBC membranes, and decrements in osmotic fragility of RBCs compared to either agent alone |
[74] | |
| MHOM/IN/1983/AG83 | Golden hamsters | Oral | At 30 days p.i., animals received oral Que (20 mg/kg) thrice a week. Hamster Salb was also injected intravenously at the same dose twice a week. Treatment was continued for 4 weeks | (i) Increasing in vivo bioavailability of Que using Que/Salb combination (ii) Superiority of Que/Salb combination over Que in preventing the accumulation of heme iron, reducing •OH in RBCs, and increasing both Hb levels and RBC lifespan |
[75] | |
| MHOM/IN/1983/AG83 | Golden hamsters | Oral | In the monotherapy study, animals received oral Que (5 to 50 mg/kg) thrice a week. In the combination therapy, Que was given orally and Salb was applied intravenously thrice a week (both at a dose of 20 mg/kg) | (i) Dose-dependent reduction in the splenic parasite burden using Que (ii) Increasing bioavailability of Que in animals subjected to the combined treatment (iii) Superiority of Que/Salb combination over Que in reducing the splenic parasite load (iv) Reduction in iron incorporation in the amastigotes collected from animals receiving the combined treatment (v) Disintegration of the amastigotes within phagolysosomes from the spleen in response to the combined treatment (vi) Remarkable reduction in the activity of ribonucleotide reductase in the amastigotes isolated from the Que/Salb-treated animals |
[76] | |
| MHOM/IN/1983/AG83 | Golden hamsters | Subcutaneous | Animals were intracardially infected with amastigotes. At 30 days p.i., they received either free Que or Que in vesicular forms (each contains 300 μg of Que intercalated in 0.5 mL of different vesicular suspensions) | (i) EC50 value of 3 mg/kg body weight for Que (ii) Reductions in the spleen parasite burden at the above-mentioned dose: free Que (26%), Que-intercalated liposomes (51%), Que-intercalated niosomes (68%), Que-intercalated nanoparticles (87%), and Que-intercalated microspheres (44%) (iii) Increasing SGPT, AP, serum urea, and creatinine levels following Que treatment. All of these levels remained close to normal in response to different vesicular forms (iv) Reducing both hepatotoxicity and renal toxicity, especially using Que-intercalated nanoparticles |
[77] | |
| MHOM/ET/67/L82 | BALB/c mice | Intraperitoneal | Animals were infected with amastigotes (in a 0.2 mL bolus via a lateral tail vein). At 7 days p.i., they received Que (30 mg/kg) for 5 consecutive days | (i) Lower in vivo efficacy of Que in comparison to 30 mg/kg of oral miltefosine (15.3% vs. 96.6%; reduction in the hepatic parasite load) | [32] | |
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| Leishmania major | MHOM/DZ/2000/LIPA1126 | BALB/c mice | Subcutaneous | Dorsal air pouches were raised on mice and were inoculated with promastigotes. The infected animals received Que (25 mg/kg) once daily for 4 days | (i) Reduction in inflammatory cell infiltration at 24 and 96 h p.i. (ii) Increasing the number of apoptotic neutrophils harboring apoptotic amastigotes at 24 and 96 h p.i. (iii) Restoring iNOS expression and activity via TNF-α stimulation in subcutaneous tissue at 24 and 96 h p.i. |
[10] |
| NM | BALB/c mice | Oral, intradermal, and intraperitoneal | Mice were intradermally infected with amastigotes. After appearance of wounds, the animal group received Que (14 mg/kg) twice a week for 4 weeks | (i) Decreasing the percentage of mortality in mice receiving Que through oral (40%), intradermal (60%), and intraperitoneal (57.14%) routes as compared to the placebo (100%) (ii) Regarding the recovery of mice from cutaneous leishmaniasis, no significant difference between Que-treated groups and Glucantime®-treated groups was observed (p = 1.00) |
[78] | |
| MHOM/IR/75/ER | Wistar rats | Intraperitoneal | Animals with infected tails received Que (50 μg/mL per kg) twice daily for 30 days | (i) Decreasing both lesion size and the number of amastigotes in mice on the 30th day of exposure to Que | [40] | |
| MRHO/IR/75/ER | BALB/c mice | Oral | Mice were injected subcutaneously at the tail base with L. major. Five weeks after inoculation, the infected mice received Que (50 mg/kg) once daily for 28 consecutive days | (i) Significant reduction in the lesion area in the Que-treated group as compared to the untreated group (p < 0.05) on the 12th day after the onset of treatment (ii) Reduction in the parasite load in the margin of cutaneous lesions in the Que-treated group (iii) Significant reduction in the number of inflammatory cells in the Que-treated group in comparison to the untreated group (p < 0.05) (iv) Formation of granulation tissue in the depth of ulcers in the Que-treated group (v) Significant increases in neovascularization, the number of both fibroblasts and fibrocytes, the levels of both FRAP and adiponectin, and GPX activity in the Que-treated group in comparison to the untreated group (p < 0.05) (vi) Significant reduction in the levels of MDA, TNF-α, and IL-6 in the Que-treated group in comparison to the untreated group (p < 0.05) |
[41] | |
| MRHO/IR/75/ER | BALB/c mice | Topical | Mice were injected subcutaneously at the tail base with promastigotes and then received luteolin/AgNPs/Que ointment containing Vaseline, AgNPs/Que (0.5%), and luteolin (0.15%) every day for 21 days | (i) Increasing the lesion size in all cases (a slight increase in the group receiving the ointment, but a significant increase in the untreated group) (ii) Acceleration of wound healing by reducing the parasitic load and inflammatory responses, particularly in mice receiving the ointment (iii) Faster wound healing process in the ointment-treated group than the Glucantime®-treated group (300 mg/mL; injection) |
[42] | |
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| Plasmodium berghei | NK65 | Swiss mice | Oral | Mice were inoculated intraperitoneally with parasitized RBCs. After 24 h, they were treated by Que (50 mg/kg), with one daily dose for three consecutive days | (i) Reducing the parasitemia by 52% and 44% on days 5 and 7 in response to Que, respectively (ii) Lower in vivo efficacy of Que in reducing the parasitemia in comparison to CHQ (20 mg/kg) |
[55] |
| NM | BALB/c mice | Intraperitoneal | Mice were inoculated intraperitoneally with parasitized RBCs. These mice were treated with NQ (10 mg/kg body), alone or in combination with HF (2 mg/kg) for 4 days | (i) Significant reduction in histopathological damage in NQ-treated infected mice as compared to the nontreated infected mice (p < 0.05) (ii) Significant reduction in the levels of proinflammatory cytokines (IL-1β and TNF-α) in NQ-treated infected mice as compared to the nontreated infected mice (p < 0.05) (iii) Superiority of NQ/HF combination over NQ in reducing both histopathological damage of P. berghei and serum levels of proinflammatory cytokines |
[79] | |
| NK65 and ANKA strains | ICR mice | Intraperitoneal | Mice were inoculated intraperitoneally with parasitized RBCs. These mice were treated with Que (2.5, 5, 10, 15, 25, and 50 mg/kg) for four consecutive days, starting at 1 h after the parasite inoculation on day 0 | (i) Suppression of parasitemia development on day 4 and prolongation of median survival in NK65-infected mice (receiving 2.5 to 50 mg/kg Que) and ANKA-infected mice (receiving 15 to 50 mg/kg Que) (ii) Lower in vivo efficacy of Que in suppressing parasitemia development on day 4 in comparison to 10 mg/kg of CHQ (iii) Significant increase in GSK3β (Ser-9) phosphorylation in the liver of NK65-infected mice (p < 0.05 vs. control) (iv) Significant increase in GSK3β (Ser-9) phosphorylation in the brain of ANKA-infected mice (p < 0.05 vs. control) (v) Reducing proinflammatory cytokines TNF-α and IFN-γ in serums of NK65-infected mice on day 4 p.i. (vi) Increasing anti-inflammatory cytokines IL-10 and IL-4 in serums of NK65-infected mice on day 4 p.i. |
[56] | |
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| Plasmodium juxtanucleare | Versiani and Gomes, 1941 | White Leghorn chicken (Gallus gallus Linnaeus, 1758) | Oral gavage | Chickens were infected with P. juxtanucleare and then were immunocompromised by the administration of MP (26 mg/kg) in the pectoral muscle. These animals were treated with Que (50 mg/kg) for four consecutive days | (i) Significant reduction in parasitemia in Que-treated group in comparison to the control group (p < 0.01) (ii) Lower in vivo efficacy of Que in reducing parasitemia in comparison to oral CHQ (50 mg/kg) |
[80] |
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| Toxoplasma gondii | Two virulent (RH, ENT) and two avirulent (ME49, C) strains | BALB/c mice | Intraperitoneal and subcutaneous | Tachyzoites were treated with AntiA and Que (50 μM) before injection into the peritoneal cavities of mice. Hsp70 expression was then assessed in T. gondii recovered from the peritoneal cavities. Moreover, spleens from subcutaneously infected mice (either treated or untreated) were collected to assess the parasite burden at 4 days p.i. | (i) Reduction in Hsp70 expression in tachyzoites of RH (87%), ENT (78%), ME49 (50%), and C strains (50%) recovering from the peritoneal cavities (ii) Reduction in the splenic burden of virulent strains (RH: 45%, ENT: 25%) with reduced Hsp70 expression (the treated virulent strains) as compared with the untreated virulent strains (iii) No significant difference in the splenic parasite burden between the untreated avirulent strains and those with reduced Hsp70 expression (the treated avirulent strains) |
[59] |
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| Babesia microti | Munich strain | BALB/c mice | Intraperitoneal | Mice were injected intraperitoneally with parasitized RBCs. These mice were treated with Que (14.5 mg/kg), and the parasitemia was then checked every day until day 22 | (i) Significant reduction in parasitemia in the Que-treated group from days 4 to 8 p.i. in comparison to the control group (p < 0.01) (ii) Lower in vivo efficacy of Que in reducing parasitemia in comparison to diminazene aceturate (25 mg/kg; intraperitoneal) |
[64] |
AntiA: antisense oligonucleotides targeting the T. gondii Hsp70 ATG start codon; AP: alkaline phosphatase; CHQ: chloroquine; EC50: the drug concentration at which the parasite load of the spleen reduced to 50%; FRAP: ferric-reducing ability of plasma; GFP: green fluorescent protein; GPX: glutathione peroxidase; GSK3β: glycogen synthase kinase-3β; Hb: hemoglobin; HF: hydroxychloroquine sulfate; Hsp70: heat shock protein 70; IFN-γ: interferon-gamma; IL-6: interleukin 6, iNOS: inducible nitric oxide synthase; LNC: lipid-core nanocapsules made of a poly-ε-caprolactone shell; MDA: malondialdehyde; mg/kg: milligrams per kilogram of body weight; MP: methylprednisolone; NM: not mentioned; NQ: nanophytosomes of quercetin; •OH: hydroxyl radical; p.i.: postinfection; Que: quercetin; RBC: red blood cell; Salb: serum albumin; SGPT: serum glutamate pyruvate transaminase; SSG: sodium stibogluconate (Pentostam®); TNF-α: tumor necrosis factor-alpha.