Abstract
This study investigated the effects of co-administration of a commercial juice rich in vitamin C (Vit C) on the antimalarial efficacy of artemether-lumefantrine (AL) in Plasmodium berghei-infected mice. Fifty Balb/c mice were infected with Plasmodium berghei NK65 strain from a donor mouse. Parasitemia was established after 72 h. Animals were grouped into 6 (n = 10) and treated daily for 3 days with normal saline, chloroquine, artemether-lumefantrine (AL), AL plus 50% commercial juice (CJ), and AL plus 50% Vit C supplementation in drinks ad libitum, respectively. Body weight, parasitemia levels, and mean survival time were determined. Tumor necrosis factor-alpha (TNF-α), interleukin 6 (IL-6), nitrite, malondialdehyde, reduced glutathione (GSH), catalase, and superoxide dismutase (SOD) were determined in the serum and liver tissues. Spleen histopathological changes were determined by H&E staining. Parasitemia was cleared by administration of AL and was not affected by Vit C and CJ supplementation. Vit C significantly prevented body weight reduction in AL-treated mice. CJ and Vit C supplementation to AL-treated mice significantly improved survival proportion compared with AL alone animals. Vit C and CJ supplementation significantly improved reduction of TNF-α, IL-6, and malondialdehyde, and increased GSH, CAT, and SOD in AL-treated mice. Spleen cell degeneration and presence of malaria pigment were reduced in AL-treated animals. The results suggest that ad libitum co-administration of commercial juice and vitamin C with artemether-lumefantrine does not impair its antimalarial efficacy but rather improved antioxidant and anti-inflammatory effects in mice.
Similar content being viewed by others
Data availability
The datasets supporting the conclusions in the article are included in the article.
References
Abiodun OO, Akinbo J, Ojurongbe O (2015) The effect of lopinavir/ritonavir on the antimalarial activity of artemether or artemether/lumefantrine in a mouse model of plasmodium berghei. J Chemother 27:1–27
Akindele SK, Ajayi MB, Aina OO, Adewale B, Oloyede AM, Akpunonu VN (2018) Effect of artemisinin-based combination therapy and chloroquine treatment on liver enzymes and biomarkers in Plasmodium berghei malaria infection in NIMR, Lagos, Nigeria. Int Res Med Sci 6(2):15–26
Albohiri H, Alzanbagi N (2021) Systemic review: The pathogenicity of Plasmodium berghei in the liver and spleen of the experimental mice. J Pharm Res Int 33(47B):515–529
Al-Obaidi MM, Taylor-Robinson AW (2017) Regulation of expression of reactive oxygen intermediates during plasmodium infection to reduce immunopathology provides a possible antioxidant adjuvant to enhance anti-malarial drug therapy. Int J Clin Microbiol 1(1):8
Ashok GR, Samruddhi M, Shreewardhan R, Mira R, Abhay C, Ranjana D (2016) Influence of MDA and pro-inflammatory cytokine levels in the pathogenesis of severe malaria in experimental murine model. Scholars Acad J Biosc 4:617–626
Avwioro OG (2010) Histochemistry and tissue pathology, principle and techniques, 2nd edn. Claverianun press, Nigeria
Becker K, Tilley L, Vennerstrom JL, Roberts D, Rogerson S, Ginsburg H (2004) Oxidative stress in malaria parasite-infected erythrocytes: host-parasite interactions. Int J Parasitol 34:163–189
Bowman ZS, Jollow DJ, McMillan DC (2005) Primaquine-induced hemolytic anemia: role of splenic macrophages in the fate of 5-hydroxyprimaquine-treated rat erythrocytes. J Pharmacol Exp Ther 315(3):980–986
Clark IA, Budd AC, Alleva LM, Cowden WB (2006) Human malarial disease: a consequence of inflammatory cytokine release. Malar J 5:85
Cobbold SA, Chua HH, Nijagal B, Creek DJ, Ralph SA, McConville MJ (2016) Metabolic dysregulation induced in Plasmodium falciparum by dihydroartemisinin and other front-line antimalarial drugs. J Infect Dis 213(2):276–286
Dantas KLS, Mota ABDSS, Silva CS, Figueiredo S, Ribeiro MRG, dos Santos Oliveira A, ... Pereira DMS (2020) Contribution of the oxidative and nitrosative stresses to the development of placental malaria and the consequences for the fetus. Revista Eletrônica Acervo Saúde, 12(9), e3784-e3784.
Dasgupta RR, Mao W, Ogbuoji O (2022) Addressing child health inequity through case management of under-five malaria in Nigeria: an extended cost-effectiveness analysis. Malar J 21(1):81
Ebenebe JC, Ntadom G, Ambe J, Wammanda R, Jiya N, Finomo F, Emechebe G, Mokuolu O, Akano K, Agomo C, Folarin OA, Oguche S, Useh F, Oyibo W, Aderoyeje T, Abdulkadir M, Ezeigwe NM, Happi C, Sowunmi A, Antimalarial Therapeutic Efficacy Monitoring Group (2018) Efficacy of artemisinin-based combination treatments of uncomplicated falciparum malaria in under-five-year-old Nigerian children ten years following adoption as first-line antimalarials. Am J Trop Med Hyg 99(3):649
Ebohon O, Irabor F, Omoregie ES (2020) Ascorbic acid coadministration with artesunate–amodiaquine, up-regulated antioxidant enzymes gene expression in bone marrow cells and elicited biochemical changes in Plasmodium berghei-infected mice. Springer Nature Appl Sci 3:6
Ebohon O, Irabor F, Omoregie ES (2021) Ascorbic acid coadministration with artesunate–amodiaquine, up-regulated antioxidant enzymes gene expression in bone marrow cells and elicited biochemical changes in Plasmodium berghei-infected mice. SN Appl Sci 3(1):1–11
Egwu CO, Augereau JM, Reybier K, Benoit-Vical F (2021) Reactive oxygen species as the brainbox in malaria treatment. Antioxidants 10(12):1872
Ekeh FN, Ekechukwu NE, Chukwuma CF, Aguzie ION, Ohanu CM, Ebido C, Oluah SN (2019) Mixed vitamin C and zinc diet supplements co-administered with artemether drug improved haematological profile and survival of mice infected with Plasmodium berghei. Food Sci Human Wellness 8(3):275–282
Ezeani UU, Osahon PT, Ezeani MC (2020) Pattern of anti-malarial drugs and artemether combination therapy adherence in an institution based medical centre, Nigeria. World J Adv Res Rev 8(3):162–170
Farombi EO, Syntum YY, Emerole GO (2003) Influence of chloroquine treatment and P. falciparum malaria infection on some enzymatic and non-enzymatic antioxidant defense indices in humans. Drug Chem Toxicol 26:59–71
Ganiyu KA, Akinleye MO, Tayo F (2012) A study of the effect of ascorbic acid on the antiplasmodial activity of artemether in Plasmodium berghei infected mice. J Appl Pharma Sci 2(6):96–100
Gomes ARQ, Cunha N, Varela ELP, Brígido HPC, Vale VV, Dolabela MF, ... Percário S (2022) Oxidative stress in malaria: potential benefits of antioxidant therapy. Int J Mol Sci 23(11), 5949
Goth L (1991) A simple method for determination of serum catalase activity and revision of reference range. Clin Chim Acta 196(2–3):143–151
Green LC, Wagner DA, Glogowski J, Skipper PL, Wishnok JS, Tannenbaum SR (1982) Analysis of nitrate, nitrite, and (15N) nitrate in bioloical fluids. Anal Biochem 126(1):131–138
Hiasindh AA, Subhash CP (2016) Antimalarial drug resistance: an overview. Trop Parasitol 6(1):30–41
Jollow DJ, Mitchell JR, Zampaglione NA, Gillette JR (1974) Bromobenzene-induced liver necrosis. Protective role of glutathione and evidence for 3, 4-bromobenzene oxide as the hepatotoxic metabolite. Pharmacology 11(3):151–169
Kassa FA, Shio MT, Bellemare MJ, Faye B, Ndao M, Olivier M (2011) New inflammation-related biomarkers during malaria infection. PLoS One 6:e26495
Kavishe RA, Koenderink JB, Alifrangis (2017) Oxidative stress in malaria and artemisinin combination therapy: pros and cons. J Fed Euro Biochem Soc 284:2579–2591
Klein EY (2013) Antimalarial drug resistance: a review of the biology and strategies to delay emergence and spread. Int J Antimicrob Agents 41:311–317
Leichtle SW, Sarma AK, Strein M, Yajnik V, Rivet D, Sima A, Brophy GM (2020) High-dose intravenous ascorbic acid: ready for prime time in traumatic brain injury? Neurocrit Care 32:333–339
Marwaha N (2016) Ascorbic acid co-administration with artemisinin-based combination therapies in falciparum malaria. J Med Res 143(5):539–541
Milner DA (2018) Malaria pathogenesis. Cold Spring Harb Perspect Med 8(1):a025569
Misra HP, Fridovich I (1972) The role of superoxide anion in the autooxidation of epinephrine and a simple assay for superoxide dismutase. J Biol Chem 247:3170–3175
Nagababu E, Rifkind JM, Sesikeran B, Lakshmaiah N (2010) Assessment of antioxidant activities of eugenol by in vitro and in vivo methods. Mol Biol 610:165–180
Oguche S, Okafor HU, Watila I, Meremikwu M, Agomo P, Ogala W, ... Sowunmi A (2014) Efficacy of artemisinin-based combination treatments of uncomplicated falciparum malaria in under-five-year-old Nigerian children. Am J Trop Med Hyg 91(5) 925
Olayemi SO, Arikawe AP, Akindele A, Oreagba AI, Awodele O (2012) Effect of malaria treatments on biochemical parameters and plasma pH of mice infected with Plasmodium berghei. Int J Pharmacol 8:549–554
Olivier M, Ham VD, Shio MT, Kassa FA, Fougeray S (2014) Malaria pigment hemozoin and the innate inflammatory response. Front Immunol 5:25
Omole MK, Oamen O (2010) A survey of the rational use of artemisinin based combination therapies (ACTs) for the treatment of malaria among health practitioners in Ogun state, South West Nigeria. Niger J Pharma Res 8(1):84–91
Onasanya SS, Ademowo OG (2013) The antimalaria effect of different dosage regimen of artemisinin-naphthoquine on Plasmodium berghei infected mice. Int J Pharmacol Ther 3(1):2249–6467
Oyinloye OE, Kosoko AM, Emikpe B, Falade CO, Ademowo OG (2015) Potential antimalarial activity of methyl jasmonate and its effect on lipid profiles in Plasmodium berghei infected mice. Afr Health Sci 15(3):841–850
Perera MK, Herath NP, Pathirana SL, Phone-Kyaw M, Alles HK, Mendis KN, ... Handunnetti SM (2013) Association of high plasma TNF-alpha levels and TNF-alpha/IL-10 ratios with TNF2 allele in severe P. falciparum malaria patients in Sri Lanka. Pathog Glob Health 107(1), 21–29
Shankar AH (2000) Nutritional modulation of malaria morbidity and mortality. J Infect Dis 182(Supplement_1):S37–S53
Shi X, Wei M, Xu Z, Liu Y, Zhang M, Lv L, Wang Q (2021) Vitamin C inhibits blood-stage plasmodium parasites via oxidative stress. Front Cell Dev Biol 9:639944
Shonhai A (2014) The role of Hsp70s in the development and pathogenicity of Plasmodium species. In: Shonhai A, Blatch G (eds) Heat shock proteins of malaria. Springer, Dordrecht, pp 47–69
Sutriana A, Asmilia N, Thasmi CN, Aliza D, Muharram W (2021) Spleen histopathological study of mice (Mus musculus) infected with Plasmodium berghei after treatment with Malacca leaves extract (Phyllantus emblica). In 2nd International Conference on Veterinary, Animal, and Environmental Sciences (ICVAES 2020) (199–203). Atlantis Press
Trivedi S, Chakravarty A (2022) Neurological complications of malaria. Curr Neurol Neurosci Rep 22(8):499–513
Vanek VW, Borum P, Buchman A, Fessler TA, Howard L, Jeejeebhoy K, Kochevar M, Shenkin A, Valentine CJ, Novel Nutrient Task Force, Parenteral Multi-Vitamin and Multi-Trace Element Working Group, American Society for Parenteral and Enteral Nutrition (ASPEN) Board of Directors (2012) ASPEN position paper: recommendations for changes in commercially available parenteral multivitamin and multi–trace element products. Nutr Clin Pract 27(4):440–491
Vasquez M, Zuniga M, Rodriguez A (2021) Oxidative stress and pathogenesis in malaria. Front Cell Infect Microbiol 11:768182
Wang J, Zhang CJ, Chia WN, Loh CC, Li Z, Lee YM, He Y, Yuan LX, Lim M, Liew CX, Lee YQ, Zhang J, Lu N, Lim CT, Hua ZC, Liu B, Shen HM, Tan KS, Lin Q (2015) Haem-activated promiscuous targeting of artemisinin in plasmodium falciparum. Nature Commun 6:10111
Wang H, Li S, Cui Z, Qin T, Shi H, Ma J, Li L, Yu G, Jiang T, Li C (2021) Analysis of spleen histopathology, splenocyte composition and haematological parameters in four strains of mice infected with Plasmodium berghei K173. Malar J 20(1):1–12
White NJ (2018) Anaemia and malaria. Malaria J 17(1):1–17
World Health Organization (2022) World malaria report 2022. World Health Organization
Zuniga M, Gomes C, Chen Z, Martinez C, Devlin JC, Loke PN, Rodriguez A (2022) Plasmodium falciparum and TNF-α differentially regulate inflammatory and barrier integrity pathways in human brain endothelial cells. Mbio 13(5):e01746-e1822
Acknowledgements
The authors acknowledge the technical assistance of Mrs. Thomas and Mrs. Braimoh of IAMRAT towards parasite inoculation and microscopy. The kind support of Dr. Olumayokun Olajide, Department of Pharmacy, University of Huddersfield, UK, towards the purchase of laboratory reagents and ELISA kits is acknowledged.
Author information
Authors and Affiliations
Contributions
AMA, IMA, and OGA conceptualized and designed the study. AMA and IMA carried out the experiment in the laboratory of OGA. AMA and IMA analyzed the data and wrote the draft manuscript.
Corresponding author
Ethics declarations
Ethics approval
Experimental procedures and protocols used in this study were approved by the University of Ibadan—Animal Care and Use Research Ethic Committee (UI-ACUREC/19/118).
Consent to participate
Not applicable.
Consent for publication
All authors read and approved the final manuscript for submission.
Conflict of interest
The authors declare no competing interests.
Additional information
Section Editor: Tobili Sam-Yellowe
Publisher's note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.
About this article
Cite this article
Ajayi, A.M., Adebanjo, I.M. & Ademowo, O.G. Vitamin C-rich juice co-administration with artemether-lumefantrine ameliorates oxido-inflammatory responses in Plasmodium berghei-infected mice. Parasitol Res 122, 1841–1850 (2023). https://doi.org/10.1007/s00436-023-07885-5
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00436-023-07885-5