Cerebral tissue oxygenation impairment during experimental cerebral malaria.

Abstract

Ischemia and hypoxia have been implicated in cerebral malaria (CM) pathogenesis, although direct measurements of hypoxia have not been conducted. C57BL/6 mice infected with Plasmodium berghei ANKA (PbA) develop a neurological syndrome known as experimental cerebral malaria (ECM), whereas BALB/c mice are resistant to ECM. In this study, intravital microscopy methods were used to quantify hemodynamic changes, vascular/tissue oxygen (O₂) tension (PO₂), and perivascular pH in vivo in ECM and non-ECM models, employing a closed cranial window model. ECM mice on day 6 of infection showed marked decreases in pial blood flow, vascular (arteriolar, venular), and perivascular PO₂, perivascular pH, and systemic hemoglobin levels. Changes were more dramatic in mice with late-stage ECM compared with mice with early-stage ECM. These changes led to drastic decreases in O₂ delivery to the brain tissue. In addition, ECM animals required a greater PO₂ gradient to extract the same amount of O₂ compared with non-infected animals, as the pial tissues extract O₂ from the steepest portion of the blood O₂ equilibrium curve. ECM animals also showed increased leukocyte adherence in postcapillary venules, and the intensity of adhesion was inversely correlated with blood flow and O₂ extraction. PbA-infected BALB/c mice displayed no neurological signs on day 6 and while they did show changes similar to those observed in C57BL/6 mice (decreased pial blood flow, vascular/tissue PO₂, perivascular pH, hemoglobin levels), non-ECM animals preserved superior perfusion and oxygenation compared with ECM animals at similar anemia and parasitemia levels, resulting in better O₂ delivery and O₂ extraction by the brain tissue. In conclusion, direct quantitative assessment of pial hemodynamics and oxygenation in vivo revealed that ECM is associated with severe progressive brain tissue hypoxia and acidosis.

• Authors: Pedro Cabrales, Yuri C Martins, Peng Kai Ong, Graziela M Zanini, John A Frangos, Leonardo J M Carvalho
• Journal: Virulence (Virulence) Vol. 4 Issue 8 Pg. 686-97 (Nov 15 2013) ISSN: 2150-5608 [Electronic] United States
• PMID: 24128424 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Topics

• Animals
• Blood Chemical Analysis
• Brain (pathology)
• Brain Chemistry
• Disease Models, Animal
• Humans
• Hydrogen-Ion Concentration
• Hypoxia (pathology)
• Malaria, Cerebral (pathology)
• Mice
• Mice, Inbred BALB C
• Mice, Inbred C57BL
• Microscopy
• Partial Pressure
• Plasmodium berghei (growth & development)