Experimental sepsis-associated encephalopathy is accompanied by altered cerebral blood perfusion and water diffusion and related to changes in cyclooxygenase-2 expression and glial cell morphology but not to blood-brain barrier breakdown

Brain Behav Immun. 2020 Jan;83:200-213. doi: 10.1016/j.bbi.2019.10.012. Epub 2019 Oct 14.


Sepsis-associated encephalopathy (SAE) refers to brain dysfunction, including delirium, occurs during severe infection and is associated with development of post-traumatic stress disorder. SAE has been proposed to be related to reduced cerebral blood flow (CBF), blood-brain barrier breakdown (BBB), white matter edema and disruption and glia cell activation, but their exact relationships remain to be determined. In the present work, we set out to study CBF using Arterial Spin Labeling (ASL) and grey and white matter structure with T2- and diffusion magnetic resonance imaging (dMRI) in rats with cecal ligation and puncture (CLP)-induced encephalopathy. Using immunohistochemistry, the distribution of the vasoactive prostaglandin-synthesizing enzyme cyclooxygenase-2 (COX-2), perivascular immunoglobulins G (IgG), aquaporin-4 (AQP4) and the morphology of glial cell were subsequently assessed in brains of the same animals. CLP induced deficits in the righting reflex and resulted in higher T2-weighted contrast intensities in the cortex, striatum and at the base of the brain, decreased blood perfusion distribution to the cortex and increased water diffusion parallel to the fibers of the corpus callosum compared to sham surgery. In addition, CLP reduced staining for microglia- and astrocytic-specific proteins in the corpus callosum, decreased neuronal COX-2 and AQP4 expression in the cortex while inducing perivascular COX-2 expression, but did not induce widespread perivascular IgG diffusion. In conclusion, our findings indicate that experimental SAE can occur in the absence of BBB breakdown and is accompanied by increased water diffusion anisotropy and altered glia cell morphology in brain white matter.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Aquaporin 4
  • Blood-Brain Barrier*
  • Cyclooxygenase 2 / biosynthesis*
  • Cyclooxygenase 2 / genetics
  • Diffusion
  • Immunoglobulin G
  • Male
  • Neuroglia / pathology*
  • Perfusion*
  • Rats
  • Rats, Wistar
  • Sepsis-Associated Encephalopathy* / blood
  • Sepsis-Associated Encephalopathy* / enzymology
  • Sepsis-Associated Encephalopathy* / metabolism
  • Sepsis-Associated Encephalopathy* / pathology
  • Water / metabolism*


  • Aquaporin 4
  • Immunoglobulin G
  • Water
  • Cyclooxygenase 2