Glutathione peroxidase contributes with heme oxygenase-1 to redox balance in mouse brain during the course of cerebral malaria

Abstract

Oxidative stress has been attributed both a key pathogenic and rescuing role in cerebral malaria (CM). In a Plasmodium berghei ANKA murine model of CM, host redox signaling and functioning were examined during the course of neurological damage. Host antioxidant defenses were early altered at the transcriptional level indicated by the gradually diminished expression of superoxide dismutase-1 (sod-1), sod-2, sod-3 and catalase genes. During severe disease, this led to the dysfunctional activity of superoxide dismutase and catalase enzymes in damaged brain regions. Vitagene associated markers (heat shock protein 70 and thioredoxin-1) also showed a decaying expression pattern that paralleled reduced expression of the transcription factors Parkinson disease 7, Forkhead box O 3 and X-box binding protein 1 with a role in preserving brain redox status. However, the oxidative stress markers reactive oxygen/nitrogen species were not accumulated in the brains of CM mice and redox proteomics and immunohistochemistry failed to detect quantitative or qualitative differences in protein carbonylation. Thus, the loss of antioxidant capacity was compensated for in all cerebral regions by progressive upregulation of heme oxygenase-1, and in specific regions by early glutathione peroxidase-1 induction. This study shows for the first time a scenario of cooperative glutathione peroxidase and heme oxygenase-1 upregulation to suppress superoxide dismutase, catalase, heat shock protein-70 and thioredoxin-1 downregulation effects in experimental CM, counteracting oxidative damage and maintaining redox equilibrium. Our findings reconcile the apparent inconsistency between the lack of oxidative metabolite build up and reported protective effect of antioxidant therapy against CM.

miR-155 Modifies Inflammation, Endothelial Activation and Blood-Brain Barrier Dysfunction in Cerebral Malaria

“…In the present study, miR-155 -/-infected mice also had significantly lower Ho-1 mRNA levels than w/t mice at d 6 post-infection. This finding is consistent with a previous study of ECM, where Ho-1 mRNA expression was found to be progressively and significantly elevated through the course of infection in multiple regions of the brain in ECM-susceptible mice (46). Even if HO-1 is associated with protection in the ECM model, this association may be lost in the absence of miR-155.…”

Glucagon-like peptide-1 analogue, liraglutide, in experimental cerebral malaria: implications for the role of oxidative stress in cerebral malaria

“…The role of ROS/RNS in the pathogenesis of ECM is indeed unclear [8, 9, 11, 12, 40, 41]. Antioxidant treatments can be protective against ECM [41] and lipid peroxidation increased and cerebral thiols decreased in late-stage ECM [40, 42, 43].…”

“…Indeed, many antioxidant treatments can also have effects on immune function [12, 46], which may partly explain their efficacy in ECM. Furthermore, although expression of some genes involved with oxidative stress is reduced in ECM [11], these seem to be compensated by increased anti-oxidant gene promotion [11, 47]: molecular markers of ROS damage (ROS-modified proteins) are largely unchanged [11, 12], mitochondrial function is preserved in ECM [8] and genetic removal of the primary endogenous reactive species generator NADPH oxidase does not improve ECM outcome [12]. Furthermore, poly(ADP-ribose) polymerase-1 knock-out mice are not protected from ECM, indicating that cytopathic hypoxia is not driving ECM [9].…”

“…haem oxygenase-1, peroxisome proliferator-activated receptor gamma coactivator 1-alpha, neuroglobin [52–54]), activation of this system in ECM may play a role in preventing ROS/RNS damage. Indeed, previous work by Linares et al [11] shows that haem oxygenase-1 is markedly increased in mice with ECM and considered an important counterweight to potential oxidative damage. The activation of the CREB system observed here might be, in part, responsible for this mechanism.…”

The immunological balance between host and parasite in malaria

“…Antioxidative treatment protects mice from CM (Thumwood et al 1989), even though no increased levels of protein carbonylation nor oxidation are found in the brain, and mice deficient in NADPH oxidase are as susceptible as WT to develop CM (Sanni et al 1999). The antioxidative defense in the brain of mice with CM appears to be mediated by HO-1 and glutathione peroxidase, whereas the expression of SOD and catalase is decreased (Linares et al 2013). Antioxidative adjunctive therapeutic treatment of severely ill P. falciparum patients was not effective (Charunwatthana et al 2009).…”