Endothelin B receptor-mediated encephalopathic events in mouse sepsis model

Abstract

Aims: We evaluated whether pathophysiological events in the brain in sepsis are mediated by ET-1/ETB receptor axis.

Main methods: We prepared raw fecal fluid from soft stool of mice. Mice were randomly divided into three groups: pre-PBS+raw fecal fluid group (Sepsis, easy stool method (ESM) group); pre-BQ788+raw fecal fluid group (BQ group); and pre-BQ788+PBS group (PBS group). According to each experimental condition, PBS or BQ788 was intravenously injected into mice prior to intraperitoneal administration of fecal fluid or PBS. All groups of mice were sacrificed at 8h after administration, and then brain samples were prepared.

Key findings: In the ESM group, an increase of apoptotic neuroblasts was demonstrated in the subgranular zone of the hippocampal dentate gyrus, enhanced expression of c-FOS was observed in arginine-vasopressin-containing neurons in the hypothalamic paraventricular nucleus, and various cytokines involving TNF-α were upregulated in the brain, compared with those in the PBS group. In the region corresponding to their findings, the number of reactive microglia and vascular leakage was markedly increased. BQ788 inhibited the induction of c-FOS expression, neuroblast apoptosis, cytokine upregulation and reactive microglia without affecting vascular leakage.

Significance: We demonstrated that BQ788 could protect the brain from the following sepsis-associated pathophysiological output: neural cell death, inflammatory response and the Hans Selye's environmental stress reaction.

Keywords: BQ788; Brain stem/progenitor cells; Hypothalamic–pituitary–adrenal axis; Sepsis-associated encephalopathy.