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A Neuroprotective Effect of the Glutamate Receptor Antagonist MK801 on Long-Term Cognitive and Behavioral Outcomes Secondary to Experimental Cerebral Malaria

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Abstract

Cerebral malaria (CM) is a life-threatening complication of Plasmodium falciparum infection, which can result in long-term cognitive and behavioral deficits despite successful anti-malarial therapy. Due to the substantial social and economic burden of CM, the development of adjuvant therapies is a scientific goal of highest priority. Apart from vascular and immune responses, changes in glutamate system have been reported in CM pathogenesis suggesting a potential therapeutic target. Based on that, we hypothesized that interventions in the glutamatergic system induced by blockage of N-methyl-D-aspartate (NMDA) receptors could attenuate experimental CM long-term cognitive and behavioral outcomes. Before the development of evident CM signs, susceptible mice infected with Plasmodium berghei ANKA (PbA) strain were initiated on treatment with dizocilpine maleate (MK801, 0.5 mg/kg), a noncompetitive NMDA receptor antagonist. On day 5 post-infection, mice were treated orally with a 10-day course chloroquine (CQ, 30 mg/kg). Control mice also received saline, CQ or MK801 + CQ therapy. After 10 days of cessation of CQ treatment, magnetic resonance images (MRI), behavioral and immunological assays were performed. Indeed, MK801 combined with CQ prevented long-term memory impairment and depressive-like behavior following successful PbA infection resolution. In addition, MK801 also modulated the immune system by promoting a balance of TH1/TH2 response and upregulating neurotrophic factors levels in the frontal cortex and hippocampus. Moreover, hippocampus abnormalities observed by MRI were partially prevented by MK801 treatment. Our results indicate that NMDA receptor antagonists can be neuroprotective in CM and could be a valuable adjuvant strategy for the management of the long-term impairment observed in CM.

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Acknowledgments

This work was supported by Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES), Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) and Rede Instituto Brasileiro de Neurociência (IBNet/FINEP), Brazil.

Author’s contribution

ASM participated in the experimental design, carried out behavioral and immunological assays, data analysis, and drafted the manuscript. FB participated in the experimental design, carried out behavioral and immunological assays, and revised the manuscript. LBV and FMR carried out glutamate release assays, data analysis, and revised the manuscript. NPR and ELMV performed immunological assays, data analysis, and revised the manuscript. PMOP performed immunological assays and revised the manuscript. GHSR and MFDM performed MRI analysis. RMR and MMT were responsible for interpretation of data and revised and edited the manuscript. FSM and MAR participated in the design and coordination of the study. ALT designed the study and was responsible for the interpretation of experiments and editing the manuscript. All authors have read and approved the final version of the manuscript.

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Authors and Affiliations

  1. Postgraduate Program in Health Sciences: Infectious Diseases and Tropical Medicine, School of Medicine, Federal University of Minas Gerais, Belo Horizonte, MG, Brazil

    Aline Silva de Miranda, Fátima Brant, Mauro Martins Teixeira, Fabiana Simão Machado & Antônio Lúcio Teixeira

  2. Laboratory of Neurobiology, Department of Morphology, Institute of Biological Sciences, Federal University of Minas Gerais, Belo Horizonte, MG, Brazil

    Aline Silva de Miranda

  3. Interdisciplinary Laboratory of Medical Investigation, School of Medicine, Federal University of Minas Gerais, Belo Horizonte, MG, Brazil

    Aline Silva de Miranda, Natália Pessoa Rocha, Érica Leandro Marciano Vieira, Mauro Martins Teixeira & Antônio Lúcio Teixeira

  4. Department of Biochemistry and Immunology, Institute of Biological Sciences, Federal University of Minas Gerais, Belo Horizonte, MG, Brazil

    Fátima Brant, Pollyana Maria de Oliveira Pimentel, Fabíola Mara Ribeiro, Mauro Martins Teixeira, Fabiana Simão Machado & Antônio Lúcio Teixeira

  5. Department of Pharmacology, Institute of Biological Sciences, Federal University of Minas Gerais, Belo Horizonte, MG, Brazil

    Luciene Bruno Vieira & Natália Pessoa Rocha

  6. Department of Physiology, Institute of Biological Sciences, Federal University of Minas Gerais, Belo Horizonte, MG, Brazil

    Gustavo Henrique Souza Rezende & Marcio F.D. Moraes

  7. Biogen Cambridge, Cambridge, MA, USA

    Richard M Ransohoff

  8. Department of Pathology, Institute of Biological Sciences, Federal University of Minas Gerais, Belo Horizonte, MG, Brazil

    Milene Alvarenga Rachid

  9. Departamento de Morfologia, ICB, UFMG, Av. Antônio Carlos, 6627, Pampulha, Belo Horizonte, 31270-901, Brazil

    Aline Silva de Miranda

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  1. Aline Silva de Miranda
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  2. Fátima Brant
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  3. Luciene Bruno Vieira
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  4. Natália Pessoa Rocha
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  5. Érica Leandro Marciano Vieira
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  8. Marcio F.D. Moraes
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  9. Fabíola Mara Ribeiro
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  10. Richard M Ransohoff
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  11. Mauro Martins Teixeira
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Corresponding author

Correspondence to Aline Silva de Miranda.

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The authors declare no conflict of interest. Dr. Ransohoff is an employee of Biogen.

Electronic supplementary material

Figure S1

Study experimental design. Briefly, C57BL/6 mice were intraperitoneally infected with 106 parasitized erythrocytes. On day 3 post-infection, a group initiated MK801 (i.p. 0.5 mg/kg) treatment, which was continued until the end of chloroquine (CQ) therapy. All mice were treated orally with a 10-day course of CQ (30 mg/kg) starting at day 5 post-infection. As controls, non-infected animals received the same volume of saline, CQ or CQ + MK801. Ten days after cessation of CQ treatment, cognitive, behavioral, and magnetic resonance images analysis were performed. Moreover, brains were also harvested for immunological and histopathological assays. (GIF 82 kb)

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Figure S2

Representative flow cytometry graphs of microglia F4/80+ CD11b+ expressing CD45 and IL10 from brain cells of C57/Bl6 mice. Cells from brain tissue from C57/Bl6 mice treated with MK801 (a) were stained and analyzed using flow cytometry as described in Materials and Methods. Flow cytometry dot-plots show the total cells (b). After selecting the cells double positive for F4/80 and CD11b (Q2 in B), CD45+ (c) was analyzed in different regions (CD45High and CD45Low) expressing IL-10 cytokine. The cytokine expression was analyzed in CD45High in F4/80+CD11b+ (D) or CD45Low in F4/80+CD11b+ (e). For all cytokine analysis, control isotypes were used for determination of cytokine expression using histogram graphs. (GIF 274 kb)

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Figure S3

Effect of MK801 on hippocampus glutamate release following Plasmodium berghei ANKA (PbA) infection resolution by chloroquine (CQ) therapy. Ten days after cessation of CQ therapy, all animals were culled, hippocampus was harvested, synaptosomes were prepared, and glutamate release in the hippocampus was measured by spectrofluorometer. Results are expressed as mean ± SEM and are representative of two independent experiments (n = 5 per group). Asterisk(s) indicate statistical differences where *p < 0.05, **p < 0.01, ***p < 0.001. (GIF 17 kb)

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Figure S4

Effect of MK801 in long-term aversive memory following Plasmodium berghei ANKA (PbA) infection resolution by chloroquine (CQ) therapy. From 10 days after cessation of CQ treatment, all mice were submitted to the step-down inhibitory avoidance test. No significant difference in the step-down latency was found in the training session or in the long-term aversive memory analyzed 24 h after training session. Results are expressed as mean ± SEM and are representative of at least two independent experiments (n = 7 per group). (GIF 26 kb)

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Figure S5

Effect of MK801 in motor and exploratory activities following Plasmodium berghei ANKA (PbA) infection resolution by chloroquine (CQ) therapy. From 10 days after cessation of CQ treatment all mice were submitted to the open field task for general motor and exploratory activities analysis. No significant differences were found in a global activity, b stereotype movements, c locomotion, d mean velocity, or e in the number of rearing episodes. Results are expressed as mean ± SEM and are representative of at least two independent experiments (n = 8 per group). (GIF 73 kb)

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Figure S6

MK801 effect in inflammatory response in the spleen of CM mice following Plasmodium berghei ANKA (PbA) infection resolution by chloroquine (CQ) therapy. Ten days after cessation of CQ therapy, all animals were culled and spleen was harvested; homogenized; and IL-2, IL-4, IL-6, IL-10, IL-17, IFN-γ, and TNF-α levels were assessed by Cytometric Bead Array (CBA). Results are expressed as mean ± SEM and are representative of at least two independent experiments (n = 5 per group). Asterisk(s) indicate statistical differences where *p < 0.05, **p < 0.01, ***p < 0.001. (GIF 182 kb)

High Resolution Image (TIFF 87 kb)

Figure S7

MK801 effect in inflammatory response in the serum of CM mice following Plasmodium berghei ANKA (PbA) infection resolution by chloroquine (CQ) therapy. Ten days after cessation of CQ therapy serum was collected and IL-2, IL-4, IL-6, IL-10, IL-17, IFN-γ, and TNF-α levels were assessed by cytometric bead array (CBA). Results are expressed as mean ± SEM and are representative of at least two independent experiments (n = 5 per group). Asterisk(s) indicate statistical differences where *p < 0.05, **p < 0.01, ***p < 0.001. (GIF 73 kb)

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de Miranda, A.S., Brant, F., Vieira, L.B. et al. A Neuroprotective Effect of the Glutamate Receptor Antagonist MK801 on Long-Term Cognitive and Behavioral Outcomes Secondary to Experimental Cerebral Malaria. Mol Neurobiol 54, 7063–7082 (2017). https://doi.org/10.1007/s12035-016-0226-3

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