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.

N-Methyl-D-Aspartate Receptors Involvement in the Gentamicin-Induced Hearing Loss and Pathological Changes of Ribbon Synapse in the Mouse Cochlear Inner Hair Cells

“…MK801 is a noncompetitive NMDA receptor antagonist that is thought to protect neurons in the brain against excitotoxicity induced by excessive glutamate activity [ 17 , 32 ]. MK801 was used as a NMDAR antagonist with the dose range from 0.2 to 1.0 (mg/kg) in previous studies [ 17 , 21 , 22 ].To explore the role of NMDARs in synaptic plasticity during ototoxicity, MK801 (0.2 mg/kg, i.p.) was used to rescue the gentamicin-induced damage.…”

“…The second group of animals received daily i.p. injections of gentamicin (100 mg/kg in saline) and the NMDAR antagonist MK801 (0.2 mg/kg in saline, Sigma-Aldrich, USA) for 4 or 7 consecutive days [ 17 , 21 , 22 ]. The mice in the third group served as the control group and received daily injections of equivalent volumes of normal saline.…”

Mesenchymal stromal cells protect against vascular damage and depression-like behavior in mice surviving cerebral malaria

“…Individuals infected with Plasmodium falciparum present a significant increase in anxiety and depression [ 4 , 36 ]. Several studies in experimental models of malaria also demonstrated anxiety and depression-like behavior alterations [ 37 – 39 ]. We also observed an increase in depression like-behavior in PbA-infected mice, while MSC treatment mitigated this behavioral alteration.…”

“…Reduced BDNF expression levels are associated with cognitive and behavioral disorders in neurological disorders, such as cerebral malaria [ 48 – 50 ]. Previous studies have showed reduced BDNF mRNA expression in the frontal cortex and the hippocampus [ 37 ] and in various brain regions, including the thalamus, hypothalamus, cerebellum, and brainstem in PbA-infected mice [ 51 ]. The downregulation of BDNF may be a point of no return for the neurological damages observed in cerebral malaria.…”

Homeostasis of the Intraparenchymal-Blood Glutamate Concentration Gradient: Maintenance, Imbalance, and Regulation

“…In an effort to ensure that “CNS security” is made an appropriate priority in pathological cases, administering a glutamate receptor antagonist following a brain insult has, in many pre-clinical studies, indicated neuro-protective roles and improved prognoses ( Furukawa et al, 2003 ; de Miranda et al, 2016 ). However, the results of clinical trials have suggested that these drugs fail to improve long-term prognoses or reduce mortality after brain injury ( Davis et al, 1997 ; Lees, 1997 ; Maas et al, 2006 ).…”