Abstract
Malaria is considered to be one of the most prevalent diseases in the world. Severity of the disease between males and females is very important in clinical research areas. In this study, we investigated the impact of sex differences in brain response to infection with Plasmodium berghei. Male and female C57Bl/6 mice were infected with P. berghei-infected erythrocytes. The infection induced a significant change in weight loss in males (−7.2 % ± 0.5) than females (−4.9 % ± 0.6). The maximum parasitemia reached about 15 % at day 9 postinfection. Also, P. berghei infection caused histopathological changes in the brain of mice. These changes were in the form of inflammation, hemorrhage, and structural changes in Purkinje cells. In addition, P. berghei was able to induce a marked oxidative damage in mice brain. The infection induced a significant increase in male brain glutathione than females while the brain catalase level was significantly increased in infected females than infected males. Moreover, the change in brain neurotransmitters, dopamine, epinephrine, norepinephrine, and serotonin, was more in infected males than infected females. At the molecular level, P. berghei was able to induce upregulations of Adam23, Cabp1, Cacnb4, Glrb, and Vdac3-mRNA in the brain of mice. These genes were significantly upregulated in infected males than in infected females. In general, P. berghei could induce structural, biochemical, and molecular alterations in mice brain. Severity of these alterations was different according to sex of mice.
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Aebi HU (ed) (1984) Methods in enzymatic analysis. Academic, New York, pp 276–286
Baptista FG, Pamplona A, Pena AC, Mota MM, Pied S, Vigário AM (2010) Accumulation of Plasmodium berghei-infected red blood cells in the brain is crucial for the development of cerebral malaria in mice. Infect Immun 78(9):4033–4039
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
Bidaud I, Mezghrani A, Swayne LA, Monteil A, Lory P (2006) Voltagegated calcium channels in genetic diseases. Biochim Biophys Acta 1763:1169–1174
Chalphin AV, Saha MS (2010) The specification of glycinergic neurons and the role of glycinergic transmission in development. Front Mol Neurosci 3:11
Ciarlone AE (1978) Further modification of a fluorometric method for analyzing brain amines. Microchem J 23:9–12
Cosgrove KP, Mazure CM, Staley JK (2007) Evolving knowledge of sex differences in brain structure, function, and chemistry. Biol Psychiatry 62(8):847–855
Darbandi-Tonkabon R, Manion BD, Hastings WR, Craigen WJ, Akk G, Bracamontes JR, He Y, Sheiko TV, Steinbach JH, Mennerick SJ, Covey DF, Evers AS (2004) Neuroactive steroid interactions with voltage-dependent anion channels: lack of relationship to GABA(A) receptor modulation and anesthesia. J Pharmacol Exp Ther 308:502–511
Delić D, Gailus N, Vohr HW, Dkhil M, Al-Quraishy S, Wunderlich F (2010) Testosterone induced permanent changes of hepatic gene expression sustained during Plasmodium chabaudi malaria. J Mol Endocrinol 45:379–390
Desruisseaux MS, Iacobas3 DA, Iacobas3 S, Mukherjee S, Weiss LM, Tanowitz HB, Spray DC (2010) Alterations in the brain transcriptome in Plasmodium berghei ANKA infected mice. J Neuroparasitology 1
Dkhil MA, Al-Quraishy S, Abdel-Baki AA, Ghanjati F, Arauzo-Bravo MJ, Delic D, Wunderlich F (2015) Epigenetic modifications of gene promoter DNA in the liver of adult female mice masculinized by testosterone. J Steroid Biochem Mol Biol 145:121–130
Dondorp AM, Angus BJ, Chotivanich K, Silamut K, Ruangveerayuth R, Hardeman MR, Kager PA, Vreeken J, White NJ (1999) Red blood cell deformability as a predictor of anemia in severe falciparum malaria. Am J Trop Med Hyg 60:733–737
Dorovini-Zis K, Schmidt K, Huynh H, Fu W, Whitten RO, Milner D, Kamiza S, Molyneux M, Taylor TE (2011) The neuropathology of fatal cerebral malaria in Malawian children. Am J Pathol 178:2146–2158
Eling W, van Zon A, Jerusalem C (1977) The course of a Plasmodium berghei infection in six different mouse strains. Z Parasitenkd 54(1):29–45
Ellman GL (1959) Tissue sulfhydryl groups. Arch Biochem Biophys 82:70–77
Franke-Fayard B, Janse CJ, Cunha-Rodrigues M, Ramesar J, Büscher P, Que I, Löwik C, Voshol PJ, den Boer MA, van Duinen SG, Febbraio M, Mota MM, Waters AP (2005) Murine malaria parasite sequestration: CD36 is the major receptor, but cerebral pathology is unlinked to sequestration. Proc Natl Acad Sci U S A 102:11468–11473
Grau GE, de Kossodo S (1994) Cerebral malaria: mediators, mechanical obstruction or more? Parasitol Today 10:408–409
Green LC, Wagner DA, Glogowski J, Skipper PL, Wishnok JS, Tannenbaum SR (1982) Analysis of nitrate, nitrite, and [15N] nitrate in biological fluids. Anal Biochem 126:131–138
Guha M, Kumar S, Choubey V, Maity P, Bandyopadhyay U (2006) Apoptosis in liver during malaria: role of oxidative stress and implication of mitochondrial pathway. FASEB J 20:439–449
Haeseleer F, Imanishi Y, Maeda T, Possin DE, Maeda A, Lee A, Rieke F, Palczewski K (2004) Essential role of Ca2+-binding protein 4, a Cav1.4 channel regulator, in photoreceptor synaptic function. Nat Neurosci 7(10):1079–1087
Hearn JN, Rayment N, Landon DN, Katz DR, de Souza JB (2000) Immunopathology of cerebral malaria: morphological evidence of parasite sequestration in murine brain microvasculature. Infect Immun 68:5364–5376
Helegbe GK, Yanagi T, Senba M, Huy NT, Shuaibu MN, Yamazaki A, Kikuchi M, Yasunami M, Hirayama K (2011) Histopathological studies in two strains of semi-immune mice infected with Plasmodium berghei ANKA after chronic exposure. Parasitol Res 108(4):807–814
Jaffar S, Van Hensbroek MB, Palmer A, Schneider G, Greenwood B (1997) Predictors of a fatal outcome following childhood cerebral malaria. Am J Trop Med Hyg 57(1):20–24
Katalinic V, Modun D, Music I, Boban M (2005) Gender differences in antioxidant capacity of rat tissues determined by 2,2′-azinobis (3-ethylbenzothiazoline 6-sulfonate; ABTS) and ferric reducing antioxidant power (FRAP) assays. Comp Biochem Physiol C Toxicol Pharmacol 140(1):47–52
Krücken J, Braun JV, Dkhil MA, Grunwald A, Wunderlich F (2005) Deletion of LTbetaR augments male susceptibility to Plasmodium chabaudi. Parasite Immunol 27(6):205–212
Livak KJ, Schmittgen TD (2001) Analysis of relative gene expression data using real-time quantitative PCR and the 2(−Delta Delta C(T)) Method. Methods 25:402–408
Medana IM, Chaudhri G, Chan-Ling T, Hunt NH (2001) Central nervous system in cerebral malaria: ‘Innocent bystander’ or active participant in the induction of immunopathology? Immunol Cell Biol 79(2):101–120
Mehlhorn H (ed) (2014) Encyclopedic reference of parasitology, vol 1, 4th edn. Springer, Berlin
Mitchell KJ, Pinson KI, Kelly OG, Brennan J, Zupicich J, Scherz P, Leighton PA, Goodrich LV, Lu X, Avery BJ, Tate P, Dill K, Pangilinan E, Wakenight P, Tessier-Lavigne M, Skarnes WC (2001) Functional analysis of secreted and transmembrane proteins critical to mouse development. Nat Genet 28:241–249
Muehlenbein MP, Alger J, Cogswell F, James M, Krogstad D (2005) The reproductive endocrine response to Plasmodium vivax infection in Hondurans. Am J Trop Med Hyg 73:178–187
Müller HE (1992) The more effective immune system of women against infectious agents. Wien Med Wochenschr 142:389–395
Munro CA, McCaul ME, Wong DF, Oswald LM, Zhou Y, Brasic J, Kuwabara H, Kumar A, Alexander M, Ye W, Wand GS (2006) Sex differences in striatal dopamine release in healthy adults. Biol Psychiatry 59:966–974
Newton CR, Krishna S (1998) Severe falciparum malaria in children: current understanding of pathophysiology and supportive treatment. Pharmacol Ther 79(1):1–53
Nishizawa S, Benkelfat C, Young SN, Leyton M, Mzengeza S, de Montigny C, Blier P, Diksic M (1997) Differences between males and females in rates of serotonin synthesis in human brain. Proc Natl Acad Sci U S A 4:5308–5313
Ohkawa H, Ohishi N, Yagi K (1979) Assay for lipid peroxides in animal tissues by thiobarbituric acid reaction. Anal Biochem 95:351–358
Omodeo-Sale MF, Motti A, Basilico N, Parapini S, Olliaro P (2003) Accelerated senescence of human erythrocytes cultured with Plasmodium falciparum. Blood 102:705–711
Postma NS, Mommers EC, Eling WMC, Zuidema J (1996) Oxidative stress in malaria: implications for prevention and therapy. Pharm World Sci 18(4):121–129
Promeneur D, Lunde LK, Amiry-Moghaddam M, Agre P (2013) Protective role of brain water channel AQP4 in murine cerebral malaria. Proc Natl Acad Sci U S A 110(3):1035–1040
Proteggente AR, England TG, Rehman A, Rice-Evans CA, Halliwell B (2002) Gender differences in steady-state levels of oxidative damage to DNA in healthy individuals. Free Radic Res 36:157–162
Reis PA, Comim CM, Hermani F, Silva B, Barichello T, Portella AC, Gomes FC, Sab IM, Frutuoso VS, Oliveira MF, Bozza PT, Bozza FA, Dal-Pizzol F, Zimmerman GA, Quevedo J, Castro-Faria-Neto HC (2010) Cognitive dysfunction is sustained after rescue therapy in experimental cerebral malaria, and is reduced by additive antioxidant therapy. PLoS Pathog 6:1–16
Rest JR (1982) Cerebral malaria in inbred mice. I. A new model and its pathology. Trans R Soc Trop Med Hyg 76(3):410–415
Roberts CW, Walker W, Alexander J (2001) Sex-associated hormones and immunity to protozoan parasites. Clin Microbiol Rev 14:476–488
Schofield L, Grau GE (2005) Immunological processes in malaria pathogenesis. Nat Rev Immunol 5:722–735
Seli E, Arici A (2002) Sex steroids and the immune system. Immunol Allergy Clin N Am 22:407–408
Tjahjani S, Bsa P, Syafruddin D, Agoes R, Hanggono T, Immaculata M (2008) Oxidative stress in Plasmodium falciparum culture incubated with artemisinin. Proc ASEAN Cong Tropl Med Parasitol 3:47–50
Tsakiris S, Schulpis KH, Marinou K, Behrakis P (2004) Protective effect of l-cysteine and glutathione on the modulated suckling rat brain Na+, K+,-ATPase and Mg2+-ATPase activities induced by the in vitro galactosaemia. Pharmacol Res 49:475–479
Vina J, Sastre J, Pallardo F, Borras C (2003) Mitochondrial theory of aging: importance to explain why females live longer than males. Antioxid Redox Signal 5:549–556
Wunderlich F, Mossmann H, Helwig M, Schillinger G (1988) Resistance to Plasmodium chabaudi in B10 mice: influence of the H-2 complex and testosterone. Infect Immun 6:2400–2406
Wunderlich F, Marinovski P, Benten WP, Schmitt-Wrede HP, Mossmann H (1991) Testosterone and other gonadal factor(s) restrict the efficacy of genes controlling resistance to Plasmodium chabaudi malaria. Parasite Immunol 13:357–367
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The authors extend appreciations to the Deanship of Scientific Research at King Saud University for funding the work through the research group project no. RGP-198.
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Figure S1
Survival of infected male and infected female C57BL/6 mice with Plasmodium berghei. n = 15. (JPEG 289 kb)
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Dkhil, M.A., Al-Shaebi, E.M., Lubbad, M.Y. et al. Impact of sex differences in brain response to infection with Plasmodium berghei . Parasitol Res 115, 415–422 (2016). https://doi.org/10.1007/s00436-015-4803-6
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DOI: https://doi.org/10.1007/s00436-015-4803-6