Adaptaquin Reduces Brain Injury After Cerebral Hypoxia- Ischemia In The Neonatal Mice

BackgroundNeonatal Hypoxic-Ischemic Brain injury is one of the most common causes of death and disability in neonatal infants,survivors often display developmental impairment and permanent neurological deficits such as cerebral palsy.Therefore,neonatal HI brain injury has seriously affected the quality life of children and brought heavily burden for their families and society.So far,only hypothermia and recombinant human erythropoietin administration have been proved to reduce disability of term or preterm brain injury.Thereby,new neuroprotective strategies are urgently needed.Hypoxia inducible factor-prolyl-4-hydroxylases(HIF-PHDs),a main regulator of hypoxia response,are important targets against mitochondria damage induced by oxidative stress in vitro and ischemic injury in vivo.Adaptaquin,a lowmolecular-weight inhibitor of the HIF-PHDs,has ability to inhibit HIF-PHDs and activate adaptive responses to hypoxia,without affecting total iron distribution in brain.Furthermore,protection of oxidative death by adaptaquin is associated with activity of protective genes.Studies have confirmed that adaptaquin penetrates the blood-brain barrier,resulting in inhibition of the oxygen-sensing HIF-PHDs.ObjectiveThe purpose of this study was to investigate the impact of Adaptaquin treatment on brain injury after cerebral Hypoxia-Ischemia in neonatal mice and to identify the possible mechanisms behind this effect.MethodsPostnatal day 9(P9)C57BL/6J mice both genders were subjected to right hemisphere HI and randomly assigned to Vehicle treatment and AQ treatment.Then pups were administrated intraperitoneally immediately after HI at the first dose of Adaptaquin(20mg/Kg)or equal volume of Vehicle,then the dose of second and third administration(10mg/Kg)was done at HI 24 h and HI 48 h,respectively.ResultsCompared with Vehicle treatment,Adaptaquin administration reduced gray matter injury and subcortical white matter injury in neonatal mice at 72 h after HI.The total infarct volume was reduced by 26.3% in AQ treatment mice,and this reduction was more pronounced in males(34.8%)than in females(11.7%).The protective effect was also more pronounced in the cortex.Subcortical white matter lost volume was reduced by 24.4% in the Adaptaquin treatment,and this reduction was also more pronounced in males(28.4%)than in females(18.9%).Adaptaquin treatment decreased neuronal cell death labeled by Fluoro-Jade in the cortex,but not in the striatum and CA1 as well as habenular nuclei.In addition,Adaptaquin increased the expression of GPX4 mRNA in the cortex.Hif1α mRNA expression also increased after HI,and adaptaquin treatment stimulated Hif1α mRNA expression,However,nuclear translocation of HIF1α protein was decreased after HI,and adaptaquin treatment had no influence on HIF1α expression in the nucleus.in the brain injury area,adaptaquin did neither alter the number of cells positive for caspase-3 activation nor AIF translocation to the nuclei.And Adaptaquin treatment had no impact on 3NT or 8-OHdG or MDA production.ConclusionIn conclusion,Adaptaquin reduced brain injury in a sex-related manner after Hypoxia-Ischemia in neonatal mice.But the behind possible mechanisms need to further investigation.