Erythropoietin increases the hypoxic sensitivity of the neural respiratory control system in newborn mice

We demonstrated previously that cerebral erythropoietin (Epo) enhances the ventilatory response under conditions of reduced oxygen availavility (hypoxia).. Specificaly, by using adult mice, we showed that Epo activates the central respiratory network under conditions of acute and chronic hypoxia. However, the impact of Epo on the respiratory control system of newborn has not yet been investigated. In this study, we hypothesized that cerebral Epo crucially affects the neural respiratory system during the postnatal development of mice. To investigate the central hypoxic sensitivity, we used the in vitro (en bloc brainstem‐spinal cord preparations ) electrophysiological technique in animals at postnatal day 4. When perfused with hypoxic artificial cerebrospinal fluid (5% CO 2 in N 2 ), Epo‐incubated brainstems showed increased time‐ and dose‐dependent phrenic activity. Moreover, this effect was dramatically reversed when bainstems were incubated with soluble Epo receptor (the Epo endogenous antagonist). To assess the effect of Epo on ventilatory response to hypoxia (RVH) in vivo , we applied the whole body plethysmography technique in mice at postnatal days P7, P10, P15 and P21. Once exposed to acute hypoxia (12%, 10% and 6% O 2 ), Epo‐treated animals at all tested ages (i.p injection of 100U Epo 12h before experimentation) showed higher ventilatory response than corresponding controls animals. These results imply that cerebral Epo plays a crucial role in the neural development of respiratory system, and suggest that Epo in brain has potential clinical implications in newborn with respiratory dysfunctions, especially in those born preterm.