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Open Access 01-12-2009 | Research

Glatiramer acetate reduces the risk for experimental cerebral malaria: a pilot study

Authors: Peter Lackner, Andrea Part, Christoph Burger, Anelia Dietmann, Gregor Broessner, Raimund Helbok, Markus Reindl, Erich Schmutzhard, Ronny Beer

Published in: Malaria Journal | Issue 1/2009

Abstract

Background

Cerebral malaria (CM) is associated with high mortality and morbidity caused by a high rate of transient or persistent neurological sequelae. Studies on immunomodulatory and neuroprotective drugs as ancillary treatment in murine CM indicate promising potential. The current study was conducted to evaluate the efficacy of glatiramer acetate (GA), an immunomodulatory drug approved for the treatment of relapsing remitting multiple sclerosis, in preventing the death of C57Bl/6J mice infected with Plasmodium berghei ANKA.

Methods and Results

GA treatment led to a statistically significant lower risk for developing CM (57.7% versus 84.6%) in treated animals. The drug had no effect on the course of parasitaemia. The mechanism of action seems to be an immunomodulatory effect since lower IFN-gamma levels were observed in treated animals in the early course of the disease (day 4 post-infection) which also led to a lower number of brain sequestered leukocytes in treated animals. No direct neuro-protective effect such as an inhibition of apoptosis or reduction of micro-bleedings in the brain was found.

Conclusion

These findings support the important role of the host immune response in the pathophysiology of murine CM and might lead to the development of new adjunctive treatment strategies.

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Schmutzhard E, Gerstenbrand F: Cerebral malaria in Tanzania. Its epidemiology, clinical symptoms and neurological long term sequelae in the light of 66 cases. Trans R Soc Trop Med Hyg. 1984, 78: 351-353. 10.1016/0035-9203(84)90118-4.CrossRefPubMed

Newton CR, Krishna S: Severe falciparum malaria in children: current understanding of pathophysiology and supportive treatment. Pharmacol Ther. 1998, 79: 1-53. 10.1016/S0163-7258(98)00008-4.CrossRefPubMed

Hunt NH, Golenser J, Chan-Ling T, Parekh S, Rae C, Potter S, Medana IM, Miu J, Ball HJ: Immunopathogenesis of cerebral malaria. Int J Parasitol. 2006, 36: 569-582. 10.1016/j.ijpara.2006.02.016.CrossRefPubMed

Hansen DS, Siomos MA, Buckingham L, Scalzo AA, Schofield L: Regulation of murine cerebral malaria pathogenesis by cd1d-restricted NKT cells and the natural killer complex. Immunity. 2003, 18: 391-402. 10.1016/S1074-7613(03)00052-9.CrossRefPubMed

Belnoue E, Kayibanda M, Vigario AM, Deschemin JC, Van Rooijen N, Viguier M, Snounou G, Renia L: On the pathogenic role of brain-sequestered alphabeta CD8+ T cells in experimental cerebral malaria. J Immunol. 2002, 169: 6369-6375.CrossRefPubMed

Lovegrove FE, Gharib SA, Patel SN, Hawkes CA, Kain KC, Liles WC: Expression microarray analysis implicates apoptosis and interferon-responsive mechanisms in susceptibility to experimental cerebral malaria. Am J Pathol. 2007, 171: 1894-1903. 10.2353/ajpath.2007.070630.PubMedCentralCrossRefPubMed

Armah HB, Wilson NO, Sarfo BY, Powell MD, Bond VC, Anderson W, Adjei AA, Gyasi RK, Tettey Y, Wiredu EK: Cerebrospinal fluid and serum biomarkers of cerebral malaria mortality in Ghanaian children. Malar J. 2007, 6: 147-10.1186/1475-2875-6-147.PubMedCentralCrossRefPubMed

Ma N, Harding AJ, Pamphlett R, Chaudhri G, Hunt NH: Increased c-fos expression in the brain during experimental murine cerebral malaria: possible association with neurologic complications. J Infect Dis. 1997, 175: 1480-1489.CrossRefPubMed

Medana IM, Chan-Ling T, Hunt NH: Reactive changes of retinal microglia during fatal murine cerebral malaria: effects of dexamethasone and experimental permeabilization of the blood-brain barrier. Am J Pathol. 2000, 156: 1055-1065.PubMedCentralCrossRefPubMed

10.

Warrell DA, Looareesuwan S, Warrell MJ, Kasemsarn P, Intaraprasert R, Bunnag D, Harinasuta T: Dexamethasone proves deleterious in cerebral malaria. A double-blind trial in 100 comatose patients. N Engl J Med. 1982, 306: 313-319.CrossRefPubMed

11.

Prasad K, Garner P: Steroids for treating cerebral malaria. Cochrane Database Syst Rev. 2000, CD000972-

12.

Kremsner PG, Grundmann H, Neifer S, Sliwa K, Sahlmuller G, Hegenscheid B, Bienzle U: Pentoxifylline prevents murine cerebral malaria. J Infect Dis. 1991, 164: 605-608.CrossRefPubMed

13.

Di PG, Di P, I Monteiro GB, Bonora S, Hennig C, Cassatella M, Micciolo R, Vento S, Dusi S, Bassetti D: Pentoxifylline as a supportive agent in the treatment of cerebral malaria in children. J Infect Dis. 1995, 171: 1317-1322.CrossRef

14.

Hemmer CJ, Hort G, Chiwakata CB, Seitz R, Egbring R, Gaus W, Hogel J, Hassemer M, Nawroth PP, Kern P: Supportive pentoxifylline in falciparum malaria: no effect on tumor necrosis factor alpha levels or clinical outcome: a prospective, randomized, placebo-controlled study. Am J Trop Med Hyg. 1997, 56: 397-403.PubMed

15.

Muniz-Junqueira MI, Silva FO, Paula-Junior MR, Tosta CE: Thalidomide influences the function of macrophages and increases the survival of Plasmodium berghei-infected CBA mice. Acta Trop. 2005, 94: 128-138. 10.1016/j.actatropica.2005.03.002.CrossRefPubMed

16.

Moreira AL, Sampaio EP, Zmuidzinas A, Frindt P, Smith KA, Kaplan G: Thalidomide exerts its inhibitory action on tumor necrosis factor alpha by enhancing mRNA degradation. J Exp Med. 1993, 177: 1675-1680. 10.1084/jem.177.6.1675.CrossRefPubMed

17.

Uadia PO, Ezeamuzie IC, Ladan MJ, Gerrets R: Antimalarial activity of cyclosporins A, C and D. Afr J Med Med Sci. 1994, 23: 47-51.PubMed

18.

Grau GE, Gretener D, Lambert PH: Prevention of murine cerebral malaria by low-dose cyclosporin A. Immunology. 1987, 61: 521-525.PubMedCentralPubMed

19.

Jennings VM, Actor JK, Lal AA, Hunter RL: Cytokine profile suggesting that murine cerebral malaria is an encephalitis. Infect Immun. 1997, 65: 4883-4887.PubMedCentralPubMed

20.

Arnon R, Aharoni R: Mechanism of action of glatiramer acetate in multiple sclerosis and its potential for the development of new applications. Proc Natl Acad Sci USA. 2004, 101 (Suppl 2): 14593-14598. 10.1073/pnas.0404887101.PubMedCentralCrossRefPubMed

21.

Teitelbaum D, Meshorer A, Hirshfeld T, Arnon R, Sela M: Suppression of experimental allergic encephalomyelitis by a synthetic polypeptide. Eur J Immunol. 1971, 1: 242-248. 10.1002/eji.1830010406.CrossRefPubMed

22.

Dhib-Jalbut S: Glatiramer acetate (Copaxone) therapy for multiple sclerosis. Pharmacol Ther. 2003, 98: 245-255. 10.1016/S0163-7258(03)00036-6.CrossRefPubMed

23.

Angelov DN, Waibel S, Guntinas-Lichius O, Lenzen M, Neiss WF, Tomov TL, Yoles E, Kipnis J, Schori H, Reuter A: Therapeutic vaccine for acute and chronic motor neuron diseases: implications for amyotrophic lateral sclerosis. Proc Natl Acad Sci USA. 2003, 100: 4790-4795. 10.1073/pnas.0530191100.PubMedCentralCrossRefPubMed

24.

Frenkel D, Maron R, Burt DS, Weiner HL: Nasal vaccination with a proteosome-based adjuvant and glatiramer acetate clears beta-amyloid in a mouse model of Alzheimer disease. J Clin Invest. 2005, 115: 2423-2433. 10.1172/JCI23241.PubMedCentralCrossRefPubMed

25.

Aharoni R, Kayhan B, Brenner O, Domev H, Labunskay G, Arnon R: Immunomodulatory therapeutic effect of glatiramer acetate on several murine models of inflammatory bowel disease. J Pharmacol Exp Ther. 2006, 318: 68-78. 10.1124/jpet.106.103192.CrossRefPubMed

26.

Schlegel PG, Aharoni R, Chen Y, Chen J, Teitelbaum D, Arnon R, Sela M, Chao NJ: A synthetic random basic copolymer with promiscuous binding to class II major histocompatibility complex molecules inhibits T-cell proliferative responses to major and minor histocompatibility antigens in vitro and confers the capacity to prevent murine graft-versus-host disease in vivo. Proc Natl Acad Sci USA. 1996, 93: 5061-5066. 10.1073/pnas.93.10.5061.PubMedCentralCrossRefPubMed

27.

Aharoni R, Teitelbaum D, Arnon R, Sela M: Copolymer 1 inhibits manifestations of graft rejection. Transplantation. 2001, 72: 598-605. 10.1097/00007890-200108270-00007.CrossRefPubMed

28.

Gorantla S, Liu J, Sneller H, Dou H, Holguin A, Smith L, Ikezu T, Volsky DJ, Poluektova L, Gendelman HE: Copolymer-1 induces adaptive immune anti-inflammatory glial and neuroprotective responses in a murine model of HIV-1 encephalitis. J Immunol. 2007, 179: 4345-4356.CrossRefPubMed

29.

Lackner P, Beer R, Heussler V, Goebel G, Rudzki D, Helbok R, Tannich E, Schmutzhard E: Behavioural and histopathological alterations in mice with cerebral malaria. Neuropathol Appl Neurobiol. 2006, 32: 177-188. 10.1111/j.1365-2990.2006.00706.x.CrossRefPubMed

30.

Lackner P, Burger C, Pfaller K, Heussler V, Helbok R, Morandell M, Broessner G, Tannich E, Schmutzhard E, Beer R: Apoptosis in experimental cerebral malaria: spatial profile of cleaved caspase-3 and ultrastructural alterations in different disease stages. Neuropathol Appl Neurobiol. 2007, 33: 560-571.PubMed

31.

Gundersen HJ, Jensen EB: The efficiency of systematic sampling in stereology and its prediction. J Microsc. 1987, 147: 229-263.CrossRefPubMed

32.

Fridkis-Hareli M, Teitelbaum D, Gurevich E, Pecht I, Brautbar C, Kwon OJ, Brenner T, Arnon R, Sela M: Direct binding of myelin basic protein and synthetic copolymer 1 to class II major histocompatibility complex molecules on living antigen-presenting cells – specificity and promiscuity. Proc Natl Acad Sci USA. 1994, 91: 4872-4876. 10.1073/pnas.91.11.4872.PubMedCentralCrossRefPubMed

33.

Neuhaus O, Farina C, Wekerle H, Hohlfeld R: Mechanisms of action of glatiramer acetate in multiple sclerosis. Neurology. 2001, 56: 702-708.CrossRefPubMed

34.

deWalick S, Amante FH, McSweeney KA, Randall LM, Stanley AC, Haque A, Kuns RD, MacDonald KP, Hill GR, Engwerda CR: Cutting edge: conventional dendritic cells are the critical APC required for the induction of experimental cerebral malaria. J Immunol. 2007, 178: 6033-6037.CrossRefPubMed

35.

Lackner P, Beer R, Helbok R, Broessner G, Engelhardt K, Brenneis C, Schmutzhard E, Pfaller K: Scanning electron microscopy of the neuropathology of murine cerebral malaria. Malar J. 2006, 5: 116-10.1186/1475-2875-5-116.PubMedCentralCrossRefPubMed

36.

Carvalho LJ, Lenzi HL, Pelajo-Machado M, Oliveira DN, Daniel-Ribeiro CT, Ferreira-da-Cruz MF: Plasmodium berghei: cerebral malaria in CBA mice is not clearly related to plasma TNF levels or intensity of histopathological changes. Exp Parasitol. 2000, 95: 1-7. 10.1006/expr.2000.4508.CrossRefPubMed

37.

Weber MS, Starck M, Wagenpfeil S, Meinl E, Hohlfeld R, Farina C: Multiple sclerosis: glatiramer acetate inhibits monocyte reactivity in vitro and in vivo. Brain. 2004, 127: 1370-1378. 10.1093/brain/awh163.CrossRefPubMed

38.

Jee Y, Liu R, Bai XF, Campagnolo DI, Shi FD, Vollmer TL: Do Th2 cells mediate the effects of glatiramer acetate in experimental autoimmune encephalomyelitis?. Int Immunol. 2006, 18: 537-544. 10.1093/intimm/dxh394.CrossRefPubMed

39.

Valenzuela RM, Costello K, Chen M, Said A, Johnson KP, Dhib-Jalbut S: Clinical response to glatiramer acetate correlates with modulation of IFN-gamma and IL-4 expression in multiple sclerosis. Mult Scler. 2007, 13: 754-762. 10.1177/1352458506074510.CrossRefPubMed

40.

Grau GE, Heremans H, Piguet PF, Pointaire P, Lambert PH, Billiau A, Vassalli P: Monoclonal antibody against interferon gamma can prevent experimental cerebral malaria and its associated overproduction of tumor necrosis factor. Proc Natl Acad Sci USA. 1989, 86: 5572-5574. 10.1073/pnas.86.14.5572.PubMedCentralCrossRefPubMed

41.

Gilgun-Sherki Y, Panet H, Holdengreber V, Mosberg-Galili R, Offen D: Axonal damage is reduced following glatiramer acetate treatment in C57/bl mice with chronic-induced experimental autoimmune encephalomyelitis. Neurosci Res. 2003, 47: 201-207. 10.1016/S0168-0102(03)00217-7.CrossRefPubMed

42.

Kipnis J, Yoles E, Porat Z, Cohen A, Mor F, Sela M, Cohen IR, Schwartz M: T cell immunity to copolymer 1 confers neuroprotection on the damaged optic nerve: possible therapy for optic neuropathies. Proc Natl Acad Sci USA. 2000, 97: 7446-7451. 10.1073/pnas.97.13.7446.PubMedCentralCrossRefPubMed

43.

Liu J, Du ZJ, Yang XG, Kuang F, Li GL, Duan XL, Wang BR: [The effect of copolymer-1 on the apoptosis and the IL-6R expression of the retinal ganglion cells in chronic elevated intraocular pressure rat model]. Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi. 2004, 20: 293-6. 300PubMed

44.

Kaiser K, Texier A, Ferrandiz J, Buguet A, Meiller A, Latour C, Peyron F, Cespuglio R, Picot S: Recombinant human erythropoietin prevents the death of mice during cerebral malaria. J Infect Dis. 2006, 193: 987-995. 10.1086/500844.CrossRefPubMed

45.

Wiese L, Hempel C, Penkowa M, Kirkby N, Kurtzhals JA: Recombinant human erythropoietin increases survival and reduces neuronal apoptosis in a murine model of cerebral malaria. Malar J. 2008, 7: 3-10.1186/1475-2875-7-3.PubMedCentralCrossRefPubMed

46.

Golenser J, McQuillan J, Hee L, Mitchell AJ, Hunt NH: Conventional and experimental treatment of cerebral malaria. Int J Parasitol. 2006, 36: 583-593. 10.1016/j.ijpara.2006.02.009.CrossRefPubMed

47.

Johnson KP, Brooks BR, Cohen JA, Ford CC, Goldstein J, Lisak RP, Myers LW, Panitch HS, Rose JW, Schiffer RB: Copolymer 1 reduces relapse rate and improves disability in relapsing-remitting multiple sclerosis: results of a phase III multicenter, double-blind placebo-controlled trial. The Copolymer 1 Multiple Sclerosis Study Group. Neurology. 1995, 45: 1268-1276.CrossRefPubMed

48.

Munari L, Lovati R, Boiko A: Therapy with glatiramer acetate for multiple sclerosis. Cochrane Database Syst Rev. 2004, CD004678-

Title: Glatiramer acetate reduces the risk for experimental cerebral malaria: a pilot study
Authors: Peter Lackner
Andrea Part
Christoph Burger
Anelia Dietmann
Gregor Broessner
Raimund Helbok
Markus Reindl
Erich Schmutzhard
Ronny Beer
Publication date: 01-12-2009
Publisher: BioMed Central
Published in: Malaria Journal / Issue 1/2009
Electronic ISSN: 1475-2875
DOI: https://doi.org/10.1186/1475-2875-8-36

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