Inhibition of hypoxia‐associated response and kynurenine production in response to hyperbaric oxygen as mechanisms involved in protection against experimental cerebral malaria

Abstract

Cerebral malaria (CM) is a multifactorial syndrome involving an exacerbated proinflammatory status, endothelial cell activation, coagulopathy, hypoxia, and accumulation of leukocytes and parasites in the brain microvasculature. Despite significant improvements in malaria control, 15% of mortality is still observed in CM cases, and 25% of survivors develop neurologic sequelae for life-even after appropriate antimalarial therapy. A treatment that ameliorates CM clinical signs, resulting in complete healing, is urgently needed. Previously, we showed a hyperbaric oxygen (HBO)-protective effect against experimental CM. Here, we provide molecular evidence that HBO targets brain endothelial cells by decreasing their activation and inhibits parasite and leukocyte accumulation, thus improving cerebral microcirculatory blood flow. HBO treatment increased the expression of aryl hydrocarbon receptor over hypoxia-inducible factor 1-α (HIF-1α), an oxygen-sensitive cytosolic receptor, along with decreased indoleamine 2,3-dioxygenase 1 expression and kynurenine levels. Moreover, ablation of HIF-1α expression in endothelial cells in mice conferred protection against CM and improved survival. We propose that HBO should be pursued as an adjunctive therapy in CM patients to prolong survival and diminish deleterious proinflammatory reaction. Furthermore, our data support the use of HBO in therapeutic strategies to improve outcomes of non-CM disorders affecting the brain.-Bastos, M. F., Kayano, A. C. A. V., Silva-Filho, J. L., Dos-Santos, J. C. K., Judice, C., Blanco, Y. C., Shryock, N., Sercundes, M. K., Ortolan, L. S., Francelin, C., Leite, J. A., Oliveira, R., Elias, R. M., Câmara, N. O. S., Lopes, S. C. P., Albrecht, L., Farias, A. S., Vicente, C. P., Werneck, C. C., Giorgio, S., Verinaud, L., Epiphanio, S., Marinho, C. R. F., Lalwani, P., Amino, R., Aliberti, J., Costa, F. T. M. Inhibition of hypoxia-associated response and kynurenine production in response to hyperbaric oxygen as mechanisms involved in protection against experimental cerebral malaria.

Kynurenine elevation correlates with T regulatory cells increase in acute Plasmodium vivax infection: A pilot study

“…IFN‐γ was shown to be essential for IDO1 induction, and mice genetically deficient for IDO1 were not protected against cerebral malaria in a P berghei ANKA (PbA) mouse model. Moreover, treatment of PbA‐infected mice with hyperbaric oxygen (HBO) conferred protection against cerebral malaria and improved survival by increasing expression of AhR and decreasing IDO1 expression and KYN metabolites …”

Hyperbaric oxygen augments susceptibility to C. difficile infection by impairing gut microbiota ability to stimulate the HIF-1α-IL-22 axis in ILC3

“…For in vivo administration of hyperbaric oxygen, 7–8-week-old mice were exposed for 90 min daily for 5 days to 100% oxygen at a pressure of 2.5 atmospheres (ATA) in a hyperbaric animal research chamber (Model HB 1300 B; Sechrist, Anaheim, CA, USA), according to a previously described protocol. 99 , 100 The chamber was pressurized and decompressed at a rate of 0.5 ATA/min. Control mice were kept in a ventilated room with normal oxygen tension and local atmospheric pressure (0.98 ATA).…”

Recent advances in the neuroprotective effects of medical gases

“…Therefore, this anti-inflammatory cytokine (IL-10) plays a crucial role in mediating the neuroprotective effect of HBO. The immediate inhalation of HBO (2.0 atmosphere absolute (ATA), 1 ATA = 1.013 kPa, 100% O 2 ) after brain injury decreases apoptosis25 and reduces the expression of inflammatory cytokines 232426. Moreover, HBO has been found to protect the integrity of the blood-brain barrier (BBB) and improve the patient prognosis 2469.…”