Periventricular leukomalacia (PVL), the dominant cerebral white matter injury disease, is induced by hypoxia-ischemia and inflammation in premature infants. The activation of A adenosine receptor (AAR) is shown to involve into inflammation, ischemia, and other typical stress reactions, but its exact function in PVL has not been clarified. We gained initial insight from PVL mouse model (P9) by the induction of hypoxia-ischemia with right carotid ligation followed by exposure to hypoxia and intraperitoneal (i.p.) injection of Lipopolysaccharide (LPS). The results showed that treatment of PSB-603, an AAR selective antagonist, greatly ameliorated cerebral ischemic injury by increasing bodyweights, reducing infarct volume, brain injury,inflammation andcontributing to long-term learning memory functionalrecoveryof the PVL mice. Meanwhile, PSB-603 treatment suppressed neurons apoptosis as characterized byreducing of Caspase-3 level, inhibited microglia activation and attenuated hypomyelination through promoting MBP expression and oligodendrocytes differentiation. AAR inhibition also augmented PKC expression, the activity of PKC downstream signaling molecules were then explored . Erk expression and Creb phosphorylation exhibited upregulation in PSB-603 treatment group compared with the control group. Hypoxia Inducible Factor-1α (HIF-1α), a direct target of hypoxia, which is a key regulator of adenosine signaling by binding to the AAR promoter to induce expression of AAR, was shown to be decreased by PSB-603. Taken together, AAR inhibition can ameliorate hypoxic-ischemic injury in PVL mice maybe through PKC/Erk/Creb/HIF-1α signaling pathway.
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