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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.
- Source :
-
Molecular neurobiology [Mol Neurobiol] 2017 Nov; Vol. 54 (9), pp. 7063-7082. Date of Electronic Publication: 2016 Oct 28. - Publication Year :
- 2017
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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.
- Subjects :
- Animals
Anxiety complications
Anxiety drug therapy
Anxiety physiopathology
Cytokines blood
Cytokines metabolism
Depression complications
Depression drug therapy
Depression physiopathology
Dizocilpine Maleate pharmacology
Excitatory Amino Acid Antagonists pharmacology
Female
Glutamic Acid metabolism
Hippocampus metabolism
Hippocampus pathology
Leukocytes metabolism
Magnetic Resonance Imaging
Malaria, Cerebral complications
Malaria, Cerebral pathology
Memory, Short-Term drug effects
Mice, Inbred C57BL
Nerve Growth Factors metabolism
Neuroprotective Agents pharmacology
Organ Size
Parasitemia blood
Parasitemia complications
Parasitemia pathology
Phenotype
Plasmodium berghei drug effects
Receptors, N-Methyl-D-Aspartate antagonists & inhibitors
Receptors, N-Methyl-D-Aspartate metabolism
Survival Analysis
Up-Regulation
Behavior, Animal drug effects
Cognition drug effects
Dizocilpine Maleate therapeutic use
Excitatory Amino Acid Antagonists therapeutic use
Malaria, Cerebral drug therapy
Malaria, Cerebral physiopathology
Neuroprotective Agents therapeutic use
Receptors, Glutamate metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1559-1182
- Volume :
- 54
- Issue :
- 9
- Database :
- MEDLINE
- Journal :
- Molecular neurobiology
- Publication Type :
- Academic Journal
- Accession number :
- 27796746
- Full Text :
- https://doi.org/10.1007/s12035-016-0226-3