title: A Neuroprotective Effect of the Glutamate Receptor Antagonist MK801 on Long-Term Cognitive and Behavioral Outcomes Secondary to Experimental Cerebral Malaria.
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.
authors: Postgraduate Program in Health Sciences: Infectious Diseases and Tropical Medicine, School of Medicine, Federal University of Minas Gerais, Belo Horizonte, MG, Brazil. mirandas.aline@gmail.com.|Laboratory of Neurobiology, Department of Morphology, Institute of Biological Sciences, Federal University of Minas Gerais, Belo Horizonte, MG, Brazil. mirandas.aline@gmail.com.|Interdisciplinary Laboratory of Medical Investigation, School of Medicine, Federal University of Minas Gerais, Belo Horizonte, MG, Brazil. mirandas.aline@gmail.com.|Departamento de Morfologia, ICB, UFMG, Av. Antônio Carlos, 6627, Pampulha, Belo Horizonte, 31270-901, Brazil. mirandas.aline@gmail.com.
authors: Aline Silva
authors: AS
authors: de Miranda
authors: Postgraduate Program in Health Sciences: Infectious Diseases and Tropical Medicine, School of Medicine, Federal University of Minas Gerais, Belo Horizonte, MG, Brazil.|Department of Biochemistry and Immunology, Institute of Biological Sciences, Federal University of Minas Gerais, Belo Horizonte, MG, Brazil.
authors: Fátima
authors: F
authors: Brant
authors: Department of Pharmacology, Institute of Biological Sciences, Federal University of Minas Gerais, Belo Horizonte, MG, Brazil.
authors: Luciene Bruno
authors: LB
authors: Vieira
authors: Interdisciplinary Laboratory of Medical Investigation, School of Medicine, Federal University of Minas Gerais, Belo Horizonte, MG, Brazil.|Department of Pharmacology, Institute of Biological Sciences, Federal University of Minas Gerais, Belo Horizonte, MG, Brazil.
authors: Natália Pessoa
authors: NP
authors: Rocha
authors: Interdisciplinary Laboratory of Medical Investigation, School of Medicine, Federal University of Minas Gerais, Belo Horizonte, MG, Brazil.
authors: Érica Leandro Marciano
authors: ÉLM
authors: Vieira
authors: Department of Physiology, Institute of Biological Sciences, Federal University of Minas Gerais, Belo Horizonte, MG, Brazil.
authors: Gustavo Henrique Souza
authors: GHS
authors: Rezende
authors: Department of Biochemistry and Immunology, Institute of Biological Sciences, Federal University of Minas Gerais, Belo Horizonte, MG, Brazil.
authors: Pollyana Maria
authors: PM
authors: de Oliveira Pimentel
authors: Department of Physiology, Institute of Biological Sciences, Federal University of Minas Gerais, Belo Horizonte, MG, Brazil.
authors: Marcio F D
authors: MFD
authors: Moraes
authors: Department of Biochemistry and Immunology, Institute of Biological Sciences, Federal University of Minas Gerais, Belo Horizonte, MG, Brazil.
authors: Fabíola Mara
authors: FM
authors: Ribeiro
authors: Biogen Cambridge, Cambridge, MA, USA.
authors: Richard M
authors: RM
authors: Ransohoff
authors: Postgraduate Program in Health Sciences: Infectious Diseases and Tropical Medicine, School of Medicine, Federal University of Minas Gerais, Belo Horizonte, MG, Brazil.|Interdisciplinary Laboratory of Medical Investigation, School of Medicine, Federal University of Minas Gerais, Belo Horizonte, MG, Brazil.|Department of Biochemistry and Immunology, Institute of Biological Sciences, Federal University of Minas Gerais, Belo Horizonte, MG, Brazil.
authors: Mauro Martins
authors: MM
authors: Teixeira
authors: Postgraduate Program in Health Sciences: Infectious Diseases and Tropical Medicine, School of Medicine, Federal University of Minas Gerais, Belo Horizonte, MG, Brazil.|Department of Biochemistry and Immunology, Institute of Biological Sciences, Federal University of Minas Gerais, Belo Horizonte, MG, Brazil.
authors: Fabiana Simão
authors: FS
authors: Machado
authors: Department of Pathology, Institute of Biological Sciences, Federal University of Minas Gerais, Belo Horizonte, MG, Brazil.
authors: Milene Alvarenga
authors: MA
authors: Rachid
authors: Postgraduate Program in Health Sciences: Infectious Diseases and Tropical Medicine, School of Medicine, Federal University of Minas Gerais, Belo Horizonte, MG, Brazil.|Interdisciplinary Laboratory of Medical Investigation, School of Medicine, Federal University of Minas Gerais, Belo Horizonte, MG, Brazil.|Department of Biochemistry and Immunology, Institute of Biological Sciences, Federal University of Minas Gerais, Belo Horizonte, MG, Brazil.
authors: Antônio Lúcio
authors: AL
authors: Teixeira
mesh_terms: D000818:Animals; D001007:Anxiety / Q000150:complications / Q000188:drug therapy / Q000503:physiopathology; D001522:Behavior, Animal / Q000187:drug effects; D003071:Cognition / Q000187:drug effects; D016207:Cytokines / Q000097:blood / Q000378:metabolism; D003863:Depression / Q000150:complications / Q000188:drug therapy / Q000503:physiopathology; D016291:Dizocilpine Maleate / Q000494:pharmacology / Q000627:therapeutic use*; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology / Q000627:therapeutic use*; D005260:Female; D018698:Glutamic Acid / Q000378:metabolism; D006624:Hippocampus / Q000378:metabolism / Q000473:pathology; D007962:Leukocytes / Q000378:metabolism; D008279:Magnetic Resonance Imaging; D016779:Malaria, Cerebral / Q000150:complications / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology*; D008570:Memory, Short-Term / Q000187:drug effects; D008810:Mice, Inbred C57BL; D009414:Nerve Growth Factors / Q000378:metabolism; D018696:Neuroprotective Agents / Q000494:pharmacology / Q000627:therapeutic use*; D009929:Organ Size; D018512:Parasitemia / Q000097:blood / Q000150:complications / Q000473:pathology; D010641:Phenotype; D010962:Plasmodium berghei / Q000187:drug effects; D017470:Receptors, Glutamate / Q000378:metabolism*; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors / Q000378:metabolism; D016019:Survival Analysis; D015854:Up-Regulation
chemical_list: D016207:Cytokines; D018691:Excitatory Amino Acid Antagonists; D009414:Nerve Growth Factors; D018696:Neuroprotective Agents; D017470:Receptors, Glutamate; D016194:Receptors, N-Methyl-D-Aspartate; D018698:Glutamic Acid; D016291:Dizocilpine Maleate
keywords: Cerebral malaria; Cytokines; Depressive-like behavior; Glutamate; MK801; Memory impairment