Dehydroepiandrosterone During Sepsis: Does the Timing of Administration Influence the Effectiveness

Abstract

Administration of dehydroepiandrosterone (DHEA) has been demonstrated to improve survival and cellular immune functions during systemic inflammation. Although there is evidence that the time point of drug application may profoundly affect the DHEA-induced effects the impact of this parameter remains to be established. Male NMRI mice were subjected to sham-operation (laparotomy) or sepsis (cecal ligation and puncture). Animals received saline or DHEA (20 mg/kg/d) given subcutaneously either 1 h before or 8 h after induction of CLP. Termination of animals was performed 48 h after induction of sepsis in order to monitor splenocyte proliferation ((3)H-thymidine incorporation assay), splenocyte apoptosis (annexin V binding capacity), and cytokine release (IL-1β and IL-6, enzyme-linked immunoassay (ELISA). DHEA administration improved the survival rate of septic mice 48 h after induction of CLP independent of the time point of application (44% versus 75% pretreatment groups; 47% versus 78% treatment groups). This effect was paralleled by a restoration of splenocyte proliferation, a decreased cellular apoptosis rate of splenocytes, and a modulation of pro-inflammatory cytokine release. Administration of DHEA either given before or after the development of clinical apparent septic symptoms reliably improves survival and cellular immune functions in a murine model of sepsis.