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Melatonin and Malaria: Therapeutic Avenues

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Melatonin and Melatonergic Drugs in Clinical Practice

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Abstract

Malaria, one of the most deadly diseases of our time, affects more than 200 million people across the globe and is responsible for about one million deaths annually. Besides Plasmodium falciparum which is the main cause for malarial infection in human beings, Plasmodium knowlesi from Malaysia also remains as the most virulent parasite spreading fast not only in Malaysia but also in different parts of the world. Global malaria eradication program by use of insecticide spraying has resulted in good response in the past. Treatment of malaria-infected patients with antimalarial drugs has helped to eliminate malarial infections successfully, but with increased resistance displayed by malarial parasites to these drugs, there is resurgence of malaria caused both by drug resistance and by infection caused by new malarial species like Plasmodium knowlesi. Recent advances on molecular studies on malarial parasites reveal that the pineal hormone melatonin acts as a cue for growth and development of Plasmodium falciparum. Same may be true for Plasmodium knowlesi also. Hence, treatment modalities that can effectively block the action of melatonin on Plasmodium species during nighttime by way of using either bright light therapy or use of melatonin receptor blocking can be considered as useful approaches for eliminating malarial infection in man.

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Abbreviations

AFMK:

N(1)-acetyl-N(2)-formyl-5-methoxykynuramine

cAMP:

Cyclic adenosine monophosphate

DDT:

Dichloro-diphenyl-trichloroethane

EM:

Erythrocyte membrane

P :

Plasmodium

Pcalp:

Plasmodium calpain

PCT:

Parasite clearance times

PfPK7:

Plasmodium falciparum protein kinase 7

PKA:

Protein kinase A

PLC:

Phospholipase C

PRR:

Parasite reduction ratio

PVM:

Parasitophorous membrane

RBC:

Red blood cell

SERA:

Serine repeat antigen (multigene family)

TBD:

Transmission-blocking drugs

UPS:

Ubiquitin-proteosome protein degradation system

References

  1. WHO, World Malaria Report: 2010, WHO Press, Geneva, Switzerland, 2010.

    Google Scholar 

  2. Sanz LM, Crespo B, De-Cozar C, Ding XC, Llergo JL, Burrows JN, et al. P. falciparum in vitro killing rates allow to discriminate between different anti-malarial mode-of-action. PLoS One. 2012;7(2):e30949.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  3. Alonso PL, Djimde A, Kremsner P, Magill A, Najera J, Plowe CV, et al. malERA Consultative Group on Drugs. A research agenda for malaria eradication: drugs. PLoS Med. 2011;8(1):e1000402. doi:10.1371/journal.pmd 1000402.

    Article  Google Scholar 

  4. Piyaphanee W, Krudsood S, Tangpukdee N, Thanachartwet W, Silachamroon U, et al. Emergence and clearance of gametocytes in uncomplicated Plasmodium falciparum malaria. Am J Trop Med Hyg. 2006;74:432–5.

    PubMed  Google Scholar 

  5. Shekalaghe S, Drakeley C, Gosling R, Ndaro A, van Meegeren M, Enevold A. Primaquine clears submicroscopic Plasmodium falciparum gametocytes that persist after treatment with sulphadoxine-pyrimethamine and artesunate. PLoS One. 2007;2:e.1023. doi:10.1371/journal.pone.0001023.

    Article  Google Scholar 

  6. Bousema T, Okell I, Shekalaghe S, Griffin JT, Omar S, Sawa P, et al. Revisiting the circulation time of Plasmodium falciparum gametocyte: molecular detection methods to estimate the duration of gametocyte carriage and the effect of gametocytocidal drugs. Malar J. 2010;9:136.

    Article  PubMed Central  PubMed  Google Scholar 

  7. Sinden RE, Carter R, Drakeley C, Leroy D. The biology of sexual development of Plasmodium: the design and implementation of transmission-blocking strategies. Malar J. 2012;11:70.

    Article  PubMed Central  PubMed  Google Scholar 

  8. Breman JG, Brandling-Bennett AD. The challenge of malaria eradication in the twenty-first century: research linked to operations is the key. Vaccine. 2011;29:D97–103.

    Article  PubMed  Google Scholar 

  9. Hotta CT, Gazarini ML, Beraldo FH, Varotti FP, Lopes C, Markus RP, et al. Calcium-dependent modulation by melatonin of the circadian rhythm in malarial parasites. Nat Cell Biol. 2000;2:466–8.

    Article  CAS  PubMed  Google Scholar 

  10. Beier J. Malaria parasite development in mosquitoes. Annu Rev Entomol. 1998;43:519–43.

    Article  CAS  PubMed  Google Scholar 

  11. Schofield L. Intravascular infiltrates and organ-specific inflammation in malaria pathogenesis. Immunol Cell Biol. 2007;85:130–7.

    Article  CAS  PubMed  Google Scholar 

  12. Gardner MJ, Hall N, Fung E, White O, Berriman M, Hyman RW, et al. Genome sequence of the human malaria parasite Plasmodium falciparum. Nature. 2002;419(6906):512–9.

    Article  PubMed  Google Scholar 

  13. Pain A, Bohme U, Berry AE, Mungall K, Finn RD, Jackson AP, et al. The genome of simian and human malaria parasite Plasmodium knowlesi. Nature. 2008;455(7214):799–803.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  14. Carlton J. The Plasmodium vivax genome sequencing project. Trends Parasitol. 2003;19(5):227–31.

    Article  CAS  PubMed  Google Scholar 

  15. Baker DA. Malaria gametocytogenesis. Mol Biochem Parasitol. 2010;172:57–65.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  16. Lasonder E, Ishihama Y, Andersen JS, Vermunt AM, Pain A, Sauerwein RW, et al. Analysis of the Plasmodium falciparum proteome by high-accuracy mass spectrometry. Nature. 2002;419:537–42.

    Article  CAS  PubMed  Google Scholar 

  17. Smith TG, Lourenco P, Carter R, Walliker D, Landford-Cartwright LC. Commitment to sexual differentiation in the human malarial parasite, Plasmodium falciparum. Parasitology. 2000;121(Pt5):127–33.

    Article  PubMed  Google Scholar 

  18. Silvestrini F, Alano P, Williams JL. Commitment to the production of male and female gametocytes in the human malarial parasite Plasmodium falciparum. Parasitology. 2000;121(Pt 5):465–71.

    Article  PubMed  Google Scholar 

  19. Trager W, Gill GS. Plasmodium falciparum gametocyte formation in vitro: its stimulation by phorbol diesters and by 8-bromo cyclic adenosine monophosphate. J Protozool. 1989;36:451–4.

    Article  CAS  PubMed  Google Scholar 

  20. Inselburg J. Stage-specific inhibitory effect of cyclic AMP on asexual maturation and gametocyte formation of Plasmodium falciparum. J Parasitol. 1983;69:592–7.

    Article  CAS  PubMed  Google Scholar 

  21. Kappe SH, Vaughen SM, Boddey JA, Cowman AF. That was then, but this is now: malaria research in the time of an eradication agenda. Science. 2010;328(5980):862–6.

    Article  CAS  PubMed  Google Scholar 

  22. Garcia CR, Markus RP, Madeira L. Tertian and quartan fevers: temporal regulation in malarial infection. J Biol Rhythms. 2001;16:436–43.

    Article  CAS  PubMed  Google Scholar 

  23. Bannister L, Mitchell G. The ins, outs, and roundabouts of malaria. Trends Parasitol. 2003;19:209–13.

    Article  PubMed  Google Scholar 

  24. Hotta CT, Markus RP, Garcia CR. Melatonin and N-acetylserotonin cross the red blood cell membrane and evoke calcium mobilization in malarial parasites. Braz J Med Biol Res. 2003;36:1583–7.

    Article  CAS  PubMed  Google Scholar 

  25. Lilburn TG, Cai H, Zhou Z, Wang Y. Protease-associated cellular networks in malaria parasite Plasmodium falciparum. BMC Genomics. 2011;12(S5):59.

    Google Scholar 

  26. Russo I, Oksman A, Vaupel B, Goldberg DE. A calpain unique to alveolates is essential in Plasmodium falciparum reveals an involvement in pre-5-phase development. Proc Natl Acad Sci U S A. 2009;106(5):1554–9.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  27. Blackman MJ. Malarial proteases and host cell egress: an ‘emerging’ cascade. Cell Microbiol. 2008;10(10):1925–34.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  28. Koyama FC, Ribeiro RY, Garcia JL, Azevedo MF, Charabarti D, Garcia CRS. Ubiquitin proteosome system and the atypical kinase PfPK7 are involved in melatonin signaling in Plasmodium falciparum. J Pineal Res. 2012. doi:10.1111/j.1600-079X.2012.00981.x.

    PubMed Central  PubMed  Google Scholar 

  29. Cohen P. Protein kinases-the major drug targets of the twenty first century. Nat Rev Drug Discov. 2002;1:309–15.

    Article  CAS  PubMed  Google Scholar 

  30. Gazharini ML, Garcia RL. Interruption of the blood stage cycle of malaria parasite, Plasmodium chabaudi by protein tyrosine kinase inhibitors. Braz J Med Biol Res. 2003;36:1465–9.

    Google Scholar 

  31. Gazarini ML, Beraldo FH, Almeida FM, Bootman FM, deSilva AM, Garcia CRS. Melatonin triggers PKA activation in the rodent malarial parasite Plasmodium chabaudi. J Pineal Res. 2011;50:64–70.

    Article  CAS  PubMed  Google Scholar 

  32. WHO. Making a difference. The World Health Report. Health Millions. 1999;25:3–5.

    Google Scholar 

  33. Wells TNC, Alonso PL, Gutteridge WE. New medicines to improve control and contribute to the eradication of malaria. Nat Rev. 2009;8:879–91.

    CAS  Google Scholar 

  34. Snow RW, Guerra CA, Noor AM, Myint HY, Hay SI. The global distribution of clinical episodes of Plasmodium falciparum malaria. Nature. 2005;434:214–7.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  35. Saleh JA, Yusuph H, Zailani SB, Ali B. Malaria vaccine: the pros and cons. Niger J Med. 2010;19(1):8–13.

    Article  CAS  PubMed  Google Scholar 

  36. Guinovart C, et al. Insights into long lasting protection induced by RTS.S/A502A malaria vaccine: further results from a phase IIb trial in Mozambican children. PLoS One. 2009;4:e5165.

    Article  PubMed Central  PubMed  Google Scholar 

  37. Robert I, Enserink M. Did they really say eradication? Science. 2007;318:1544–5.

    Article  Google Scholar 

  38. Singh B, Kim Sung L, Matusop A, Radhakrishnan A, Shamsul SS, Cox-Singh J, et al. A large focus of naturally acquired Plasmodium knowlesi infections in human beings. Lancet. 2004;363:1017–24.

    Article  PubMed  Google Scholar 

  39. Sabbatani S, Fiorino S, Manfredi R. Plasmodium knowlesi: from Malaysia, a novel health care threat. Infez Med. 2012;1:5–11.

    Google Scholar 

  40. Daneshvar C, Davis TME, Cox-Singh J, Rafa’ee MZ, Zakaria SK, Divis PC, et al. Clinical and laboratory features of human Plasmodium knowlesi infection. Clin Infect Dis. 2009;49:852–60.

    Article  PubMed Central  PubMed  Google Scholar 

  41. Cox-singh J, Hiu J, Lucas SB, Divis PC, Zulkarnaen M, Chandran P, et al. Severe malaria-a case of fatal Plasmodium knowlesi infection with post-mortem findings: a case report. Malar J. 2010;9:1–7.

    Article  Google Scholar 

  42. Vythilingam I. Plasmodium knowlesi in humans: a review on the role of its vectors in Malaysia. Trop Biomed. 2010;27(1):1–12.

    PubMed  Google Scholar 

  43. Vythilingam I, NoorAzian YM, Huat TC, Ida Jiram A, Yusri YM, Azahari AH, et al. Plasmodium knowlesi in humans, macaques and mosquitoes in Peninsular Malaysia. Parasit Vectors. 2008;1:26. doi:10.1186/1756-3305-1-26.

    Article  PubMed Central  PubMed  Google Scholar 

  44. Daneshwar C, Davis TME, Cox-Singh J, Rafa’ee MZ, Zakaria SK, Divis PC, et al. Clinical and parasitological response to oral chloroquine and primaquine in uncomplicated human Plasmodium knowlesi infections. Malar J. 2010;9:238–44.

    Article  Google Scholar 

  45. O’Neill PM, Barton VE, Ward SA. The molecular mechanism of action of artemisinin-the debate continues. Molecules. 2010;15:1705–21.

    Article  PubMed  Google Scholar 

  46. Gujjar R, Marwaha A, El Mazouni F, White J, White KL, Creason S, et al. Identification of a metabolically stable triazolopyrimidine-based dihydroorotate dehydrogenase inhibitor with anti malarial activity in mice. J Med Chem. 2009;52:1864–72.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  47. Klonis N, Crespo-Ortis MP, Bottova I, Abu-Baker N, Kenney S, Rosenthal PJ, et al. Artemisinin activity against Plasmodium falciparum requires haemoglobin uptake and digestion. Proc Natl Acad Sci U S A. 2011;108:11405–10.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  48. Kumura N, Furukawa H, Onyango AN, Izumi M, Nakajima S, Ito H, et al. Different behaviour of artemisinin and tetraoxane in the oxidative degradation of phospholipid. Chem Phys Lipids. 2009;160:114–20.

    Article  CAS  PubMed  Google Scholar 

  49. Delves M, Plouffe D, Scheurer C, Meister S, Wittlin S, Winzeler EA, et al. The activities of current antimalarial drugs on the life cycle stages of Plasmodium. PLoS Med. 2012;9(2):e1001169.

    Article  PubMed Central  PubMed  Google Scholar 

  50. Wilairatana P, Tangpukdee N, Krudsood S. Longterm primaquine administration to reduce Plasmodium falciparum gametocyte transmission in hypoendemic areas. Southeast Asian J Top Med Public Health. 2010;41:1306–11.

    CAS  Google Scholar 

  51. Shekalaghe SA, Drakeley C, van den Bosch S, ter Braak R, van den Bijllardt W, Mwanziva C, et al. A cluster randomized trial of mass drug administration with a gametocytocidal drug combination to interrupt malaria transmission in a low endemic area in Tanzania. Malar J. 2011;10:247.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  52. Hardeland R, Cardinali DP, Srinivasan V, Spence DW, Brown GM, Pandi-Perumal SR. Melatonin-A pleiotropic, orchestering regulator molecule. Prog Neurobiol. 2011;93(3):350–84.

    Article  CAS  PubMed  Google Scholar 

  53. Florens L, Washburn MP, Raine JD, Anthony RM, Grainger M, Haynes JD, et al. A proteomic view of the Plasmodium falciparum life cycle. Nature. 2002;419:520–6.

    Article  CAS  PubMed  Google Scholar 

  54. Beraldo FH, Garcia CRS. Products of tryptophan metabolism induce Ca2+ release and modulate the cell cycle of Plasmodium falciparum malarial parasites. J Pineal Res. 2005;39:224–30.

    Article  CAS  PubMed  Google Scholar 

  55. Beraldo AH, Mikoshiba K, Garcia CR. Human malarial parasite Plasmodium falciparum displays a capacitative entry: 2 aminoethyl diphenylborinate blocks the signal transduction pathway of melatonin on P. falciparum cell cycle. J Pineal Res. 2007;43:360–4.

    Article  CAS  PubMed  Google Scholar 

  56. Alves E, Barlett PJ, Garcia CRS, Thomas A. Melatonin and IP3 release from intracellular stores in the Malaria Parasite Plasmodium falciparum within increased red blood cells. J Biol Chem. 2011;286(7):5905–12.

    Article  CAS  PubMed  Google Scholar 

  57. Balzer I, Hardeland R. Photoperiodism and effects of indoleamines in a unicellular algae. Gonyaulax polyedra. Science. 1991;253:795–7.

    Article  CAS  PubMed  Google Scholar 

  58. Macías M, Rodríguez-Cabezas MN, Reiter RJ, Osuna A, Acuña-Castroviejo D. Presence and effects of melatonin in Trypanosoma cruzi J Pineal Res. 1999;27(2):86–94.

    Google Scholar 

  59. Saigusa T, Ishizaki S, Watabiki S, Ishil N, Tanakadate A, Tamai V, et al. Circadian behavioural rhythm in Caenorhabditis elegans. Curr Biol. 2002;12:R46–7.

    Article  CAS  PubMed  Google Scholar 

  60. Tanaka D, Furusawa K, Kameyama K, Okamoto H, Doi M. Melatonin signalling regulates locomotion behaviour and homeostatic states through distinct pathways in Caenorhabditis elegans. Neuropharmacology. 2007;53:157–68.

    Article  CAS  PubMed  Google Scholar 

  61. Sack RL. Host melatonin secretion is timing signal for the release of W. bancrofti. Med Hypotheses. 2009;73:147–9.

    Article  CAS  PubMed  Google Scholar 

  62. Srinivasan V, Ahmed AH, Mohamed M, Zakariah R. Melatonin effects on Plasmodium falciparum life cycle; a new avenue for therapeutic approach. Recent Pat Endocr Metab Immune Drug Discov. 2012;6(2):139–47.

    Article  CAS  PubMed  Google Scholar 

  63. Lewy AJ, Wehr TA, Goodwin FK, Newsome DA, Markey SP. Light suppresses melatonin secretion in humans. Science. 1980;210:1267–9.

    Article  CAS  PubMed  Google Scholar 

  64. Ando K, Kripke DF, Cole RJ, Elliott JA. Light mask 500 lux treatment for delayed sleep phase syndrome. Prog Neuropsychopharmacol Biol Psychiatry. 1999;23:15–24.

    Article  CAS  PubMed  Google Scholar 

  65. Colbaugh ME, Timothy A. System and method for delivering electromagnetic radiation to the eyeball of a subject. US 2012/0041520 A1 dated, 16 Feb 2012.

    Google Scholar 

  66. Garcia CRS, De Azevedo MF, Wunderlich G, Budu A, Young JA, Bannister L. Plasmodium in the postgenomic era: new insights into the molecular cell biology of malaria parasites. Int Rev Cell Mol Biol. 2008;266:85–156.

    Article  CAS  PubMed  Google Scholar 

  67. Abate K. Modern day malaria: an overview of this lingering threat. Adv Nurse Pract. 2008;16:67–8.

    PubMed  Google Scholar 

  68. Siddiqui NJ, Pandey VC. Studies on hepatic oxidative stress and anti oxidative defense system during arteether treatment of Plasmodium yoelii nigeriensis infected mice. Mol Cell Biochem. 1999;196:169–73.

    Article  Google Scholar 

  69. Guha M, Maity P, Choubey V, Mitra K, Reiter RJ, Bandyopadhyay U. Melatonin inhibits free-radical mediated mitochondrial-dependent hepatocyte apoptosis and liver damage induced during malarial infection. J Pineal Res. 2007;43:372–81.

    Article  CAS  PubMed  Google Scholar 

  70. Srinivasan V, Spence DW, Moscovitch A, Pandi-Perumal SR, Trakht I, Brown GM, et al. Malaria: therapeutic implications of melatonin. J Pineal Res. 2010;48:1–8.

    Article  CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. Sri Sathya Sai Medical Educational and Research Foundation, An International Medical Sciences Research Study Center, Prasanthi Nilayam, 40-Kovai Thirunagar Extn, Goldwins, Coimbatore, Tamilnadu, 641014, India

    Venkataramanujam Srinivasan MSc, PhD, MAMS

  2. National Health Service, Department of Mental Health, Psychiatric Service of Diagnosis and Treatment, Hospital “G. Mazzini”, ASL 4, Teramo, Italy

    Venkataramanujam Srinivasan MSc, PhD, MAMS

  3. Department of Neuroscience and Imaging, University “G.D’ Annunzio”, Chieti, 66013, Italy

    Venkataramanujam Srinivasan MSc, PhD, MAMS

  4. Department of Physiology, School of Medical Sciences, Universiti Sains Malaysia, Kubang Kerian, Kelantan, 16150, Malaysia

    Mahaneem Mohamed MD, MSc, PhD, Rahimah Zakaria MBBS, MSc, PhD (Physiology) & Asma Hayati Ahmad MBBS, MSc

  5. School of Heath Sciences, Universiti Sains Malaysia, Health Campus, Kubang Kerian, Kelantan, 16150, Malaysia

    Rozieyati Mohamed Saleh DPhil

Authors
  1. Venkataramanujam Srinivasan MSc, PhD, MAMS
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  2. Mahaneem Mohamed MD, MSc, PhD
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  3. Rahimah Zakaria MBBS, MSc, PhD (Physiology)
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  4. Asma Hayati Ahmad MBBS, MSc
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  5. Rozieyati Mohamed Saleh DPhil
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Corresponding author

Correspondence to Venkataramanujam Srinivasan MSc, PhD, MAMS .

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Editors and Affiliations

  1. Sri Sathya Sai Medical Educational and Research Foundation, An International Medical Sciences Research Center, Coimbatore, Tamil Nadu, India

    V. Srinivasan

  2. Department of Obstetrics and Gynecology, Hadassah Hebrew-University Medical Center, Jerusalem, Israel

    Amnon Brzezinski

  3. Department of Physiology, Gulhane Military Medical Academy, Ankara, Turkey

    Sukru Oter

  4. Department of Psychiatry Behavioral Sciences, Mercer University School of Medicine, Macon, Georgia, USA

    Samuel D. Shillcutt

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Srinivasan, V., Mohamed, M., Zakaria, R., Ahmad, A.H., Saleh, R.M. (2014). Melatonin and Malaria: Therapeutic Avenues. In: Srinivasan, V., Brzezinski, A., Oter, S., Shillcutt, S. (eds) Melatonin and Melatonergic Drugs in Clinical Practice. Springer, New Delhi. https://doi.org/10.1007/978-81-322-0825-9_12

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