RESUMO
Cerebral malaria (CM) is a severe complication resulting from Plasmodium falciparum infection that might cause permanent neurological deficits. Cannabidiol (CBD) is a nonpsychotomimetic compound of Cannabis sativa with neuroprotective properties. In the present work, we evaluated the effects of CBD in a murine model of CM. Female mice were infected with Plasmodium berghei ANKA (PbA) and treated with CBD (30mg/kg/day - 3 or 7days i.p.) or vehicle. On 5th day-post-infection (dpi), at the peak of the disease), animals were treated with single or repeated doses of Artesunate, an antimalarial drug. All groups were tested for memory impairment (Novel Object Recognition or Morris Water Maze) and anxiety-like behaviors (Open field or elevated plus maze test) in different stages of the disease (at the peak or after the complete clearance of the disease). Th1/Th2 cytokines and neurotrophins (brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF)) were measured in the prefrontal cortex and hippocampus of experimental groups. PbA-infected mice displayed memory deficits and exhibited increase in anxiety-like behaviors on the 5dpi or after the clearance of the parasitemia, effects prevented by CBD treatment. On 5dpi, TNF-α and IL-6 increased in the hippocampus, while only IL-6 increased in the prefrontal cortex. CBD treatment resulted in an increase in BDNF expression in the hippocampus and decreased levels of proinflammatory cytokines in the hippocampus (TNF-α) and prefrontal cortex (IL-6). Our results indicate that CBD exhibits neuroprotective effects in CM model and might be useful as an adjunctive therapy to prevent neurological symptoms following this disease.
Assuntos
Antimaláricos/farmacologia , Canabidiol/farmacologia , Cognição/efeitos dos fármacos , Malária Cerebral/tratamento farmacológico , Fármacos Neuroprotetores/farmacologia , Plasmodium berghei , Animais , Ansiedade/tratamento farmacológico , Ansiedade/fisiopatologia , Artemisininas/farmacologia , Artesunato , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Cognição/fisiologia , Modelos Animais de Doenças , Quimioterapia Combinada , Feminino , Hipocampo/efeitos dos fármacos , Hipocampo/fisiopatologia , Malária Cerebral/fisiopatologia , Malária Cerebral/psicologia , Transtornos da Memória/tratamento farmacológico , Transtornos da Memória/fisiopatologia , Camundongos Endogâmicos C57BL , Fator de Crescimento Neural/metabolismo , Córtex Pré-Frontal/efeitos dos fármacos , Córtex Pré-Frontal/fisiopatologia , Análise de Sobrevida , Resultado do TratamentoRESUMO
Cognitive dysfunction is a major sign of cerebral malaria (CM). However, the underlying mechanisms of CM cognitive outcome remain poorly understood. A body of evidence suggests that adult neurogenesis may play a role in learning and memory processes. It has also been reported that these phenomena can be regulated by the immune system. We hypothesized that memory dysfunction in CM results from hippocampal neurogenesis impairment mediated by the deregulated immune response during the acute phase of CM. C57Bl/6 mice were infected with Plasmodium berghei ANKA (PbA) strain, using a standardized inoculation of 10(6) parasitized erythrocytes. Long-term working memory was evaluated using the novel object recognition test. The mRNA expression of brain-derived neurotrophic factor (BDNF), tropomyosin-receptor-kinase (TRK-B) and nerve growth factor (NGF) in the frontal cortex and hippocampus was estimated by real-time polymerase chain reaction (PCR). The protein levels of cytokine interleukin-2 (IL-2), IL-4, IL-6, IL-10, interferon-γ (IFN-γ), tumor necrosis factor-α (TNF-α), and CCL11 and neurotrophins BDNF and NGF were determined using a cytometric bead array (CBA) kit or enzyme-linked immunosorbent assay. Cell viability in the hippocampus was analyzed by Confocal Microscopy. Neurogenesis in the dentate gyrus was determined through quantification of doublecortin (DCX) positive cells. PbA-infected mice presented working memory impairment on day 5 post-infection. At this same time point, CM mice exhibited a decrease in DCX-positive cells in the dentate gyrus in parallel with increased cell death and elevated inflammatory cytokines (IL-6, TNF-α, IFN-γ and CCL11) in the hippocampus and frontal cortex. A significant reduction of BDNF mRNA expression was also found. IL-6 and TNF-α correlated negatively with BDNF and NGF levels in the hippocampus of CM mice. In summary, we provide further evidence that neuroinflammation following PbA-infection influences neurotrophin expression, impairs adult hippocampal neurogenesis and increases hippocampal cell death in association with memory impairment following CM course. The current study identified potential mediators of memory impairment in CM.