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Evaluation of chalcone derivatives for their role as antiparasitic and neuroprotectant in experimentally induced cerebral malaria mouse model

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Abstract

Cerebral malaria is a severe complication of Plasmodium falciparum infection with a complex pathophysiology. The current course of treatment is ineffective in lowering mortality or post-treatment side effects such as neurological and cognitive abnormalities. Chalcones are enormously distributed in spices, fruits, vegetables, tea, and soy-based foodstuffs that are well known for their antimalarial activity, and in recent years they have been widely explored for brain diseases like Alzheimer's disease. Therefore, considering the previous background of chalcones serving as both antimalarial and neuroprotective, the present study aimed to study the effect of these chalcone derivatives on an experimental model of cerebral malaria (CM). CM-induced mice were tested behaviorally (elevated plus maze, rota rod test, and hanging wire test), biochemically (nitric oxide estimation, cytokines (IL-1, IL-6, IL-10, IL-12p70, TNF, IFN-y), histopathologically and immunohistochemically, and finally ultrastructural changes were examined using a transmission electron microscope. All three chalcones treated groups showed a significant (p < 0.001) decrease in percentage parasitemia at the 10th day post-infection. Mild anxiolytic activity of chalcones as compared to standard treatment with quinine has been observed during behavior tests. No pigment deposition was observed in the QNN-T group and other chalcone derivative treated groups. Rosette formation was seen in the derivative 1 treated group. The present derivatives may be pioneered by various research and science groups to design such a scaffold that will be a future antimalarial with therapeutic potential or, because of its immunomodulatory properties, it could be used as an adjunct therapy.

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Data availability

The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.

Abbreviations

ANOVA:

One-way analysis of variance

BBB:

Blood brain barrier

CM:

Cerebral malaria

CMC:

Carboxymethyl cellulose

COX-2:

Cyclooxygenase-2

CPCSEA:

Committee for the Purpose of Control and Supervision of Experiments on Animals

DPX:

Dibutylphthalate polystyrene xylene

ECM:

Experimental cerebral malaria

EPM:

Elevated plus maze

ICAM-1:

Intercellular adhesion molecule 1

IFN ‐γ:

Interferon-gamma

IL-1β:

Interleukin-1 beta

iNOS:

Inducible nitric oxide synthase

LPS:

Lipopolysaccharide

NF-kB:

Nuclear factor kappa B

NLRP3:

NOD-, LRR- and pyrin domain-containing protein 3)

NO:

Nitric Oxide

OsO4 :

Osmium tetroxide

pRBCs:

Parasitized red blood cells

QNN-T:

Quinine treated

RBCs:

Red blood cells

SPSS:

Statistical package for the social sciences

TLR 4:

Toll-like receptor 4

TNF-α:

Tumour necrosis factor alpha

References

  • Attemene S, Beourou S, Tuo K et al (2018) Antiplasmodial activity of two medicinal plants against clinical isolates of Plasmodium falciparum and Plasmodium berghei infected mice. J Parasit Dis 42(1):68–76

    Article  PubMed  Google Scholar 

  • Bruneel F (2019) Human cerebral malaria: 2019 mini review. Rev Neurol (paris) 175(7–8):445–450

    Article  CAS  PubMed  Google Scholar 

  • Cariaco Y, Lima WR, Sousa R et al (2018) Ethanolic extract of the fungus Trichoderma stromaticum decreases inflammation and ameliorates experimental cerebral malaria in C57BL/6 mice. Sci Rep 8(1):1547

    Article  PubMed  PubMed Central  Google Scholar 

  • Chen M, Brøgger Christensen S, Zhai L et al (1997) The novel oxygenated chalcone, 2,4-dimethoxy-4’-butoxychalcone, exhibits potent activity against human malaria parasite Plasmodium falciparum in vitro and rodent parasites Plasmodium berghei and Plasmodium yoelii in vivo. J Infect Dis 176(5):1327–1333

    Article  CAS  PubMed  Google Scholar 

  • Chen YF, Wu SN, Gao JM et al (2020) The antioxidant, anti-inflammatory, and neuroprotective properties of the synthetic chalcone derivative AN07. Molecules (basel, Switzerland) 25(12):2907

    Article  CAS  PubMed  Google Scholar 

  • Cho S, Kim S, Jin Z et al (2011) Isoliquiritigenin, a chalcone compound, is a positive allosteric modulator of GABAA receptors and shows hypnotic effects. Biochem Biophys Res Commun 413(4):637–642

    Article  CAS  PubMed  Google Scholar 

  • Cooke JP (2004) The pivotal role of nitric oxide for vascular health Can. J Cardiol 20:7B-15B

    Google Scholar 

  • Dal Piaz F, Braca A, Belisario MA, De Tommasi N (2010) Thioredoxin system modulation by plant and fungal secondary metabolites. Curr Med Chem 17(5):479–494

    Article  Google Scholar 

  • de Oca MM, Engwerda C, Haque A (2013) Plasmodium berghei ANKA (PbA) infection of C57BL/6J mice: a model of severe malaria. Methods Mol Biol 1031:203–213

    Article  PubMed  Google Scholar 

  • Dixit SK, Yadav N, Kumar S, Good L, Awasthi SK (2014) Synthesis and antibacterial activity of fluoroquinoone analogs. Med Chem Res 23(12):5237–5249

    Article  CAS  Google Scholar 

  • Domínguez JN, Charris JE, Lobo G et al (2001) Synthesis of quinolinyl chalcones and evaluation of their antimalarial activity. Eur J Med Chem 36(6):555–560

    Article  PubMed  Google Scholar 

  • Dunst J, Kamena F, Matuschewski K (2017) Cytokines and chemokines in cerebral malaria pathogenesis. Front Cell Infect Microbiol 7:324

    Article  PubMed  PubMed Central  Google Scholar 

  • Go ML, Liu M, Wilairat P et al (2004) Antiplasmodial chalcones inhibit sorbitol-induced hemolysis of Plasmodium falciparum-infected erythrocytes. Antimicrob Agents Chemother 48(9):3241–3245

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Gomes MN, Muratov EN, Pereira M et al (2017) Chalcone derivatives: promising starting points for drug design. Molecules 22:1210

    Article  PubMed  PubMed Central  Google Scholar 

  • Gyengesi E, Munch G (2020) In search of an anti-inflammatory drug for Alzheimer disease. Nat Rev Neurol 16:131–132

    Article  CAS  PubMed  Google Scholar 

  • Hattori K, Lee H, Hurn PD et al (2000) Cognitive deficits after focal cerebral ischemia in mice. Stroke 3:1939–1944

    Article  Google Scholar 

  • Higgs J, Wasowski C, Marcos A et al (2019) Chalcone derivatives: synthesis, in vitro and in vivo evaluation of their anti-anxiety, anti-depression and analgesic effects. Heliyon 5(3):e01376

    Article  PubMed  PubMed Central  Google Scholar 

  • Higuchi K, Watanabe T, Tanigawa T et al (2010) Sofalcone, a gastroprotective drug, promotes gastric ulcer healing following eradication therapy for Helicobacter pylori: a randomized controlled comparative trial with cimetidine, an H2-receptor antagonist. J Gastroenterol Hepatol 25(Suppl 1):S155-160

    Article  CAS  PubMed  Google Scholar 

  • Honda H, Nagai Y, Matsunaga T et al (2014) Isoliquiritigenin is a potent inhibitor of NLRP3 inflammasome activation and diet-induced adipose tissue inflammation. J Leukoc Biol 96:1087–1100

    Article  PubMed  Google Scholar 

  • Jain K, Sood S, Gowthamarajan K (2013) Modulation of cerebral malaria by curcumin as an adjunctive therapy. Braz J Infect Dis 17(5):579–591

    Article  PubMed  PubMed Central  Google Scholar 

  • Jiwrajka M, Phillips A, Butler M, Rossi M, Pocock JM (2016) The plant-derived chalcone 2,2′,5′-trihydroxychalcone provides neuroprotection against toll-like receptor 4 triggered inflammation in microglia. Oxid Med Cell Longev 2016:6301712

    Article  PubMed  Google Scholar 

  • John CC, Kutamba E, Mugarura K, Opoka RO (2010) Adjunctive therapy for cerebral malaria and other severe forms of Plasmodium falciparum malaria. Expert Rev Anti Infect Ther 8(9):997–1008

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kingston DGI, Cassera MB (2022) Antimalarial natural products. Prog Chem Org Nat Prod 117:1–106

    CAS  PubMed  Google Scholar 

  • Lee YH, Jeon SH, Kim SH et al (2012) A new synthetic chalcone derivative, 2-hydroxy-3′,5,5′-trimethoxychalcone (DK-139), suppresses the toll-like receptor 4-mediated inflammatory response through inhibition of the Akt/NF-kappaB pathway in BV2 microglial cells. Exp Mol Med 44:369–377

    Article  PubMed  PubMed Central  Google Scholar 

  • Lin YM, Zhou Y, Flavin MT et al (2002) Chalcones and flavonoids as anti-tuberculosis agents. Bioorg Med Chem 10(8):2795–2802

    Article  CAS  PubMed  Google Scholar 

  • Lyke KE, Burges R, Cissoko Y et al (2004) Serum levels of the proinflammatory cytokines interleukin-1 beta (IL-1beta), IL-6, IL-8, IL-10, tumor necrosis factor alpha, and IL-12(p70) in Malian children with severe Plasmodium falciparum malaria and matched uncomplicated malaria or healthy controls. Infect Immun 72(10):5630–5637

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Mateeva N, Gangapuram M, Mazzio E et al (2015) Biological evaluation of synthetic chalcone and flavone derivatives as anti-inflammatory agents. Med Chem Res 24:1672–1680

    Article  CAS  PubMed  Google Scholar 

  • Medana IM, Turner GD (2006) Human cerebral malaria and the blood-brain barrier. Int J Parasitol 36(5):555–568

    Article  CAS  PubMed  Google Scholar 

  • Mimche PN, Taramelli D, Vivas L (2011) The plant-based immunomodulator curcumin as a potential candidate for the development of an adjunctive therapy for cerebral malaria. Malar J 10:S1–S10

    Article  Google Scholar 

  • Mojzis J, Varinska L, Mojzisova G, Kostova I, Mirossay L (2008) Anti-angiogenic effects of flavonoids and chalcones. Pharmacol Res 57(4):259–265

    Article  CAS  PubMed  Google Scholar 

  • Mturi N, Musumba CO, Wamola BM, Ogutu BR, Newton CR (2003) Cerebral malaria: optimising management. CNS Drugs 17(3):153–165

    Article  CAS  PubMed  Google Scholar 

  • Nowakowska Z (2007) A review of anti-infective and anti-inflammatory chalcones. Eur J Med Chem 42(2):125–137

    Article  CAS  PubMed  Google Scholar 

  • Obermeier B, Daneman R, Ransohoff RM (2013) Development, maintenance and disruption of the blood-brain barrier. Nat Med 19(12):1584–1596

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ouji M, Augereau JM, Paloque L, Benoit-Vical F (2018) Plasmodium falciparum resistance to artemisinin-based combination therapies: a sword of Damocles in the path toward malaria elimination. Parasite 25:24

    Article  PubMed  PubMed Central  Google Scholar 

  • Radu M, Chernoff J (2013) An in vivo assay to test blood vessel permeability. J vis Exp 73:e50062

    Google Scholar 

  • Rani A, Singh A, Kaur J et al (2021) 1H–1,2,3-triazole grafted tacrine-chalcone conjugates as potential cholinesterase inhibitors with the evaluation of their behavioral tests and oxidative stress in mice brain cells. Bioorg Chem 114:105053

    Article  CAS  PubMed  Google Scholar 

  • Rudin W, Eugstewr HP, Bordmann G et al (1997) Resistance to cerebral malaria in tumor necrosis factor-alpha-deficient mice is associated with a reduction of intercellular adhesion molecule-1 up-regulation and T helper type 1 response. Am J Pathol 150(1):257–266

    CAS  PubMed  PubMed Central  Google Scholar 

  • Sahu NK, Balbhadra SS, Choudhary J, Kohli DV (2012) Exploring pharmacological significance of chalcone scaffold: a review. Curr Med Chem 19:209–225

    Article  CAS  PubMed  Google Scholar 

  • Salehi B, Quispe C, Chamkhi I et al (2021) Pharmacological properties of chalcones: a review of preclinical including molecular mechanisms and clinical evidence. Front Pharmacol 11:592654

    Article  PubMed  PubMed Central  Google Scholar 

  • Sanni LA, Fonseca LF, Langhorne J (2002) Mouse models for erythrocytic-stage malaria. Methods Mol Med 72:57–76

    CAS  PubMed  Google Scholar 

  • Serirom S, Raharjo WH, Chotivanich K et al (2003) Anti-adhesive effect of nitric oxide on Plasmodium falciparum cytoadherence under flow. Am J Pathol 162(5):1651–1660

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Shiotsuki H, Yoshimi K, Shimo Y et al (2010) A rotarod test for evaluation of motor skill learning. J Neurosci Methods 189(2):180–185

    Article  PubMed  Google Scholar 

  • Sinha S, Medhi B, Sehgal R (2013) Chalcones as an emerging lead molecule for antimalarial therapy: a review. J Modern Med Chem 1(2):64–77

    Google Scholar 

  • Sinha S, Batovska DI, Medhi B et al (2019) In vitro anti-malarial efficacy of chalcones: cytotoxicity profile, mechanism of action and their effect on erythrocytes. Malar J 18(1):421

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sinha S, Radotra BD, Medhi B et al (2020) Ultrastructural alterations in Plasmodium falciparum induced by chalcone derivatives. BMC Res Notes 13(1):290

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sinha S, Prakash A, Medhi B et al (2021) Pharmacokinetic evaluation of chalcone derivatives with antimalarial activity in New Zealand white rabbits. BMC Res Notes 14(1):264

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sriwilaijaroen N, Liu M, Go ML, Wilairat P (2006) Plasmepsin II inhibitory activity of alkoxylated and hydroxylated chalcones. Southeast Asian J Trop Med Public Health 37(4):607–612

    CAS  PubMed  Google Scholar 

  • Sun J, Zhang X, Broderick M, Fein H (2003) Measurement of nitric oxide production in biological systems by using Griess reaction assay. Sensors 3(8):276–284

    Article  CAS  Google Scholar 

  • Thapa P, Upadhyay SP, Suo WZ et al (2021) Chalcone and its analogs: Therapeutic and diagnostic applications in Alzheimer’s disease. Bioorg Chem 108:104681

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Tomar V, Bhattacharjee G, Rajakumar S, Srivastava K, Puri S (2010) Synthesis of new chalcone derivatives containing acridinyl moiety with potential antimalarial activity. Eur J Med Chem 45:745–751

    Article  CAS  PubMed  Google Scholar 

  • Tousoulis D, Kampoli AM, Tentolouris C, Papageorgiou N, Stefanadis C (2012) The role of nitric oxide on endothelial function. Curr Vasc Pharmacol 10(1):4–18

    Article  CAS  PubMed  Google Scholar 

  • van der Heyde HC, Nolan J, Combes V et al (2006) A unified hypothesis for the genesis of cerebral malaria: sequestration, inflammation and hemostasis leading to microcirculatory dysfunction. Trends Parasitol 22(11):503–508

    Article  PubMed  Google Scholar 

  • Walf AA, Frye CA (2007) The use of the elevated plus maze as an assay of anxiety-related behavior in rodents. Nat Protoc 2(2):322–328

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wang W, Qian H, Cao J (2015) Stem cell therapy: a novel treatment option for cerebral malaria? Stem Cell Res Ther 6(1):141

    Article  PubMed  PubMed Central  Google Scholar 

  • Wisner-Gebhart AM, Brabec RK, Gray RH (1980) Morphometric studies of chloroquine-induced changes in hepatocytic organelles in the rat. Exp Mol Pathol 33(2):144–152

    Article  CAS  PubMed  Google Scholar 

  • Xu QX, Hu Y, Li GY, Xu W, Zhang YT, Yang XW (2018) Multi-target anti-alzheimer activities of four prenylated compounds from psoralea fructus. Molecules 23:614

    Article  PubMed  PubMed Central  Google Scholar 

  • Yeo TW, Lampah DA, Gitawati R et al (2007) Impaired nitric oxide bioavailability and l-arginine reversible endothelial dysfunction in adults with falciparum malaria. J Exp Med 204(11):2693–2704

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zhang M, Wu Y, Xie L et al (2018) Isoliquiritigenin protects against blood-brain barrier damage and inhibits the secretion of pro-inflammatory cytokines in mice after traumatic brain injury. Int Immunopharmacol 65:64–75

    Article  CAS  PubMed  Google Scholar 

  • Zhu X, Liu J, Chen S et al (2019) Isoliquiritigenin attenuates lipopolysaccharide-induced cognitive impairment through antioxidant and anti-inflammatory activity. BMC Neurosci 20:41

    Article  PubMed  PubMed Central  Google Scholar 

  • Ziegler HL, Hansen HS, Staerk D et al (2004) The antiparasitic compound licochalcone a is a potent echinocytogenic agent that modifies the erythrocyte membrane in the concentration range where antiplasmodial activity is observed. Antimicrob Agents Chemother 48(10):4067–4071

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

We are thankful to ICMR, New Delhi for providing financial support in form of junior research fellowship and senior research fellowship to Shweta Sinha. Special thanks are given to Upma Bagai, Professor, Punjab University, Chandigarh for providing the P. berghei ANKA strain and technical staff of CSIC, Post Graduate Institute of Medical Education & Research, Chandigarh, India, for allowing the use of sophisticated instruments.

Funding

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

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Authors and Affiliations

  1. Department of Medical Parasitology, Post Graduate Institute of Medical Education and Research, Chandigarh, 160012, India

    Shweta Sinha & Rakesh Sehgal

  2. Department of Pharmacology, Post Graduate Institute of Medical Education and Research, Chandigarh, India

    Bikash Medhi

  3. Department of Histopathology, Post Graduate Institute of Medical Education and Research, Chandigarh, India

    B. D. Radotra

  4. Institute of Organic Chemistry with Centre of Phytochemistry, Bulgarian Academy of Sciences, Sofia, Bulgaria

    Daniela Batovska & Nadezhda Markova

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  1. Shweta Sinha
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Contributions

RS, BM, BDR and SS designed the study. SS carried out the experiment and wrote the initial draft of the manuscript. BDR examined the Histopathological and IHC Data. All authors SS, RS, BDR, BM, DIB and NM did the final editing of manuscript and agreed to the publication of this study.

Corresponding author

Correspondence to Rakesh Sehgal.

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Conflict of interest

The authors declare that they have no competing interests.

Ethical approval

The ethical approval was taken from the Institutional Animal Ethics Committee, Postgraduate Institute of Medical Education and Research, Chandigarh, Reference No. 69/IAEC/418 as per the Committee for the Purpose of Control and Supervision of Experiments on Animals (CPCSEA) guidelines.

Supplementary Information

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13205_2023_3676_MOESM1_ESM.jpg

Supplementary File 1. Induced CM in C57BL/6 mice. Step 1: Inoculation of 0.2 mL containing 106 of P. berghei ANKA infected erythrocytes. Step 2: A) Thin smear of P. berghei ANKA infected erythrocytes stained with Giemsa and observed under 1000 X oil immersion on 10th post-infection. B) Graph to show linear progression of infection in terms of percentage parasitemia from day 3rd till 10th post-infection. ***p<0.001 vs day 3rd post-infection (n=3). Step 3: Histopathological features of tissues stained with hematoxylin and eosin : A) Brain at 400 X magnification B) Brain at 1000X magnification and C) Liver D) Spleen E)Lung F)Kidney sections of P. berghei ANKA infected mice model at 400 X magnifications. The black arrow indicates deposition of malaria pigment (hemozoin) (JPG 149 KB)

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Sinha, S., Medhi, B., Radotra, B.D. et al. Evaluation of chalcone derivatives for their role as antiparasitic and neuroprotectant in experimentally induced cerebral malaria mouse model. 3 Biotech 13, 260 (2023). https://doi.org/10.1007/s13205-023-03676-y

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