A infecção por Plasmodium berghei (ANKA) induz um quadro de encefalopatia hepática em modelo murino de malária não complicada

Abstract

Introduction. The main changes in hepatocellular dysfunction associated with malaria are liver failure, hepatosplenomegaly and increased liver enzymes. Several studies have already elucidated that such liver changes can be caused by increased ammonia levels, which can consequently lead to dysfunction in the central nervous system (CNS), causing hepatic encephalopathy, culminating in an increase in the inflammatory response, cerebral edema, deregulation of neurotransmitters and cognitive and locomotor changes. Objective: To characterize possible changes in the central nervous system resulting from liver injury induced by Plasmodium berghei ANKA infection in a murine model of uncomplicated malaria. Methodology. For this, mice of the Balb-c lineage (20- 25g) were used between 45-54 postnatal days (CEUA nº 2229290317), inoculated with ~106 parasitized erythrocytes intraperitoneally. The experimental design was divided into two parts: Firstly, the survival curve, parasitemia, body mass, clinical signs, hepatic and histological changes, neurochemistry, presence of cerebral edema, vascular extravasation, inflammatory response, behavioral changes and quantification of blood levels were characterized. ammonia in the control and PbA groups. Subsequently, a treatment with lactulose was carried out to verify whether the changes found in the previous experiments were due to the increase in ammonia levels in the animals' brains. For this purpose, the groups were divided into: control group, lactulose 3mg/kg, PbA and PbA+lactulose 3mg/kg, in which the survival curve, parasitemia and locomotor activity were evaluated using the SHIRPA protocol. The results were expressed as mean+standard deviation. ANOVA (one way) was performed, post Tukey test, considering p<0.05 as significant. Results. Our data demonstrated that the PbA group presented changes in liver functions such as increased levels of AST and ALP, BT and BD, morphological changes such as hepatosplenomegaly, in addition to histological changes showing inflammatory infiltrate, deposition of malarial pigment and Kupffer cell hyperplasia, thus demonstrating a picture of liver failure. After characterizing the liver injury, we sought to understand whether these changes could generate impairment in the CNS, which we observed cognitive and motor impairment, in addition to changes in the levels of the neurotransmitters GABA and glutamate, accompanied by an increase in the inflammatory response, cerebral edema and dysfunction in the liver. blood-brain barrier. Once liver failure was demonstrated and, consequently, the presence of cognitive and behavioral changes, we sought to evaluate ammonia levels in the brains of control and PbA animals in the initial phase of infection. In this sense, the quantification of ammonia levels showed an increase on the 10th d.p.i., in brain tissue when compared to the control group, in which the levels were within expectations in relation to locomotor activity, when applying the protocol in the infected and treated group with lactulose, it was possible to observe that the PbA group showed changes in motor behavior, when compared to the control group. In contrast, the PbA+Lactulose 3mg/kg group showed an attenuation of cognitive and behavioral changes, showing that therapy with lactulose can attenuate the cognitive condition regarding motor behavior, muscle strength and tone, reflexes, and sensory function. Conclusion. We conclude that liver failure causes hepatic encephalopathy in a murine model of uncomplicated malaria, which culminates in changes in the central nervous system, by increasing ammonia levels in the brain, and by sequestering ammonia with the help of treatment. with lactulose at a dose of 3mg/kg, it can attenuate the neurological damage of animals with uncomplicated malaria, demonstrating that the behavioral changes come from a condition of hepatic encephalopathy, caused by increased levels of ammonia in the cortex of infected animals.