RESUMO
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.
Assuntos
Comportamento Animal , Cognição , Maleato de Dizocilpina/uso terapêutico , Antagonistas de Aminoácidos Excitatórios/uso terapêutico , Malária Cerebral/tratamento farmacológico , Malária Cerebral/fisiopatologia , Fármacos Neuroprotetores/uso terapêutico , Receptores de Glutamato/metabolismo , Animais , Ansiedade/complicações , Ansiedade/tratamento farmacológico , Ansiedade/fisiopatologia , Comportamento Animal/efeitos dos fármacos , Cognição/efeitos dos fármacos , Citocinas/sangue , Citocinas/metabolismo , Depressão/complicações , Depressão/tratamento farmacológico , Depressão/fisiopatologia , Maleato de Dizocilpina/farmacologia , Antagonistas de Aminoácidos Excitatórios/farmacologia , Feminino , Ácido Glutâmico/metabolismo , Hipocampo/metabolismo , Hipocampo/patologia , Leucócitos/metabolismo , Imageamento por Ressonância Magnética , Malária Cerebral/complicações , Malária Cerebral/patologia , Memória de Curto Prazo/efeitos dos fármacos , Camundongos Endogâmicos C57BL , Fatores de Crescimento Neural/metabolismo , Fármacos Neuroprotetores/farmacologia , Tamanho do Órgão , Parasitemia/sangue , Parasitemia/complicações , Parasitemia/patologia , Fenótipo , Plasmodium berghei/efeitos dos fármacos , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , Receptores de N-Metil-D-Aspartato/metabolismo , Análise de Sobrevida , Regulação para CimaRESUMO
Given the known effects of undernutrition over protein synthesis, we promoted neonatal undernutrition to evaluate its effect over the neuroplasticity induced by the pilocarpine model of epilepsy and also over spontaneous seizure expression. A well-nourished group (WN), fed ad libitum rat chow diet, and an undernourished group (UN), fed 60% of the amount of diet consumed by a WN group, were submitted to status epilepticus (SE) through pilocarpine injection at 45 days of age. Thereafter, animals were behaviorally monitored for 6h daily to quantify seizures. On the 120th day, electroencephalography (EEG) was recorded and rats were sacrificed to measure proteins and glutamate release from hippocampus. Neo-Timm staining was used to detect mossy fiber sprouting. The results indicate no statistical difference in the latency for the first spontaneous recurrent seizure (SRS), in the number of daily SRS, or in EEG epileptiform activity duration between groups. However, PILO promoted more K(+)-stimulated glutamate release in the hippocampus slices from WN animals when compared to the UN group. It was also found a lower degree of mossy fibers sprouting in UN group. Data from this work, thus, indicate that the decreased neuroplasticity as currently measured does not directly impact on the manifestation of spontaneous seizures.