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

• Published in: Molecular neurobiology 2017-11, Vol.54 (9), p.7063-7082
• Main Authors: de Miranda, Aline Silva, Brant, Fátima, Vieira, Luciene Bruno, Rocha, Natália Pessoa, Vieira, Érica Leandro Marciano, Rezende, Gustavo Henrique Souza, de Oliveira Pimentel, Pollyana Maria, Moraes, Marcio F.D., Ribeiro, Fabíola Mara, Ransohoff, Richard M, Teixeira, Mauro Martins, Machado, Fabiana Simão, Rachid, Milene Alvarenga, Teixeira, Antônio Lúcio
• Format: Article
• Language: English
• Subjects: Animals; Anxiety - complications; Anxiety - drug therapy; Anxiety - physiopathology; Behavior; Behavior, Animal - drug effects; Biomedical and Life Sciences; Biomedicine; Cell Biology; Chloroquine; Clinical outcomes; Cognition - drug effects; Cognitive ability; Cortex (frontal); Cytokines - blood; Cytokines - metabolism; Depression - complications; Depression - drug therapy; Depression - physiopathology; Dizocilpine; Dizocilpine Maleate - pharmacology; Dizocilpine Maleate - therapeutic use; Excitatory Amino Acid Antagonists - pharmacology; Excitatory Amino Acid Antagonists - therapeutic use; Female; Glutamatergic transmission; Glutamic Acid - metabolism; Glutamic acid receptors (ionotropic); Hippocampus; Hippocampus - metabolism; Hippocampus - pathology; Immune response; Immune system; Immunological memory; Immunology; Impairment; Infections; Leukocytes - metabolism; Long term memory; Lymphocytes T; Magnetic Resonance Imaging; Malaria; Malaria, Cerebral - complications; Malaria, Cerebral - drug therapy; Malaria, Cerebral - pathology; Malaria, Cerebral - physiopathology; Memory, Short-Term - drug effects; Mice; Mice, Inbred C57BL; N-Methyl-D-aspartic acid receptors; Nerve Growth Factors - metabolism; Neurobiology; Neurology; Neurons; Neuroprotection; Neuroprotective Agents - pharmacology; Neuroprotective Agents - therapeutic use; Neurosciences; Neurotransmitters; Neurotrophic factors; Organ Size; Parasitemia - blood; Parasitemia - complications; Parasitemia - pathology; Phenotype; Plasmodium berghei - drug effects; Receptors, Glutamate - metabolism; Receptors, N-Methyl-D-Aspartate - antagonists & inhibitors; Receptors, N-Methyl-D-Aspartate - metabolism; Rodents; Survival Analysis; Up-Regulation; Vector-borne diseases
• ISSN: 0893-7648; 1559-1182
• DOI: 10.1007/s12035-016-0226-3

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.