TY - JOUR
T1 - A Neuroprotective Effect of the Glutamate Receptor Antagonist MK801 on Long-Term Cognitive and Behavioral Outcomes Secondary to Experimental Cerebral Malaria
AU - de Miranda, Aline Silva
AU - Brant, Fátima
AU - Vieira, Luciene Bruno
AU - Rocha, Natália Pessoa
AU - Vieira, Érica Leandro Marciano
AU - Rezende, Gustavo Henrique Souza
AU - de Oliveira Pimentel, Pollyana Maria
AU - Moraes, Marcio F.D.
AU - Ribeiro, Fabíola Mara
AU - Ransohoff, Richard M.
AU - Teixeira, Mauro Martins
AU - Machado, Fabiana Simão
AU - Rachid, Milene Alvarenga
AU - Teixeira, Antônio Lúcio
N1 - Publisher Copyright:
© 2016, Springer Science+Business Media New York.
PY - 2017/11/1
Y1 - 2017/11/1
N2 - 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.
AB - 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.
KW - Cerebral malaria
KW - Cytokines
KW - Depressive-like behavior
KW - Glutamate
KW - Memory impairment
KW - MK801
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UR - http://www.scopus.com/inward/citedby.url?scp=84992730302&partnerID=8YFLogxK
U2 - 10.1007/s12035-016-0226-3
DO - 10.1007/s12035-016-0226-3
M3 - Article
C2 - 27796746
AN - SCOPUS:84992730302
SN - 0893-7648
VL - 54
SP - 7063
EP - 7082
JO - Molecular Neurobiology
JF - Molecular Neurobiology
IS - 9
ER -