The effect of creatine (Cr) on the response of the respiratory center to anoxia was analyzed at different postnatal stages in a brainstem slice preparation of mice. Spontaneous rhythmic activity was recorded from hypoglossal rootlets (XII) and from identified neurons within the preBötzinger complex using the whole cell patch clamp technique. The hypoxic response was evaluated in slices from animals (n= 46), which received normal nutrition (controls,n= 16), from litters of animals fed with Cr (2 g/kg/day; nutrition group,n= 8), or after incubating slices for 3 h in Cr (200 μM) (incubation group,n= 22). ATP was measured in slices from controls and Cr-incubated slices which underwent 30-min anoxia. In neonatal animals (P0-5), amplitudes of hypoglossal bursts increased initially during anoxia by 14% in controls and by 41% in Cr-supplemented animals when compared with preanoxic values. Hypoglossal burst duration increased by 3% in controls, but by 18% in the Cr-nutrition group. In brainstem slices, the initial increase of amplitudes changed from 14%(controls) to 59% (Cr incubation) and prolongation of bursts from 3%(controls) to 37% (Cr incubation) compared with preanoxic values. In juvenile controls (P6-13), burst amplitude and duration increased by 12 and 14% during early anoxia when referred to preanoxic values. In slices from Cr-pretreated animals, increases of 48% (amplitude) and 21% (burst duration) occurred. The ATP levels remained constant during a 30-min anoxic period in the Cr-pretreated group compared with a decrease of 44% in slices from controls. Our data suggest that Cr can ameliorate hypoxic energy failure. Further studies will examine the neuroprotective potential in humans.Abbreviations: aCSF,artificial cerebrospinal fluid;Cr,creatine;PCr,phosphocreatine;XII,hypoglossal rootlets;NMDA,N-methyl-D-aspartate;preBÖTc,preBötzinger complex