Protective Effect Of Histamine H₂ Receptor Antagonism On Neonatal Hypoxic-ischemic White Matter Injury And The Involved Mechanisms

Neonatal hypoxic-ischemic encephalopathy（NHIE）with the pathological characteristic of white matter injury often leads to life-long cognitive and neurobehavioral dysfunction,but relevant therapies to promote remyelination are still unavailable.It has been reported that H₂ receptor（H₂R）participates in white matter injury induced by experimental allergic encephalomyelitis,and its expression presents in late stage of embryonic development,suggesting that the H₂R may be involved in neonatal hypoxic-ischemic white matter injury.Here,we employed pharmacological approach,virus mediated overexpression or knockdown,and transgenic mice generated by Cre-loxp system to investigate the role of H₂R in hypoxic-ischemic white matter injury.We found that H₂R antagonists promoted oligodendrocyte remyelination and the recovery of motor and cognition functions in rotarod and object recognition tests and Morris water maze tests following neonatal hypoxia-ischemia,but had no effect on the demyelination.Furthermore,we found that H₂R antagonist increased the number of O4⁺differentiating oligodendrocytes,but not the NG2⁺oligodendrocyte precursor cells（OPCs）.All the effects can be reversed by H₂R agonist.Furthermore,we found that H₂R antagonists also promoted oligodendrocyte differentiation and remyelination following neonatal hypoxia-ischemia,even with a delayed or shortened administration regimen.Moreover,we discovered that H₂R overexpression negatively regulated oligodendrocyte differentiation after oxygen-glucose deprivation（OGD）in vitro,while H₂R knockdown promoted the oligodendrocyte differentiation.Finally,we generated the mice with selective deletion of the H₂R gene（Hrh2）in differentiating oligodendrocytes(Hrh2^fl/fl;CNPase-Cre)by Cre-loxp system.We found that Hrh2^fl/fl;CNPase-Cre mice showed comparable demyelinated level,but improved oligodendrocyte differentiation,remyelination,and functional recovery in rotarod and object recognition tests and Morris water maze tests following neonatal hypoxia-ischemia.In summary,our results demonstrated that H₂R antagonism promotes oligodendrocyte differentiation,remyelination and the functional recovery after neonatal hypoxic-ischemic white matter injury.H₂R antagonists may be potential drugs for the treatment of white matter injury in NHIE.