A2B adenosine receptor inhibition ameliorates hypoxic-ischemic injury in neonatal mice via PKC/Erk/Creb/HIF-1α signaling pathway.

[Display omitted] • Hypoxia-ischemia with LPS impaired myelination in developing brains of mice. • Blocking of A 2B AR with PSB-603 attenuated cerebral white matter injury in mice with PVL. • Blocking of A 2B AR with PSB-603 promoted myelination and functional recovery in adult mice with PVL via the PKC/Erk/Creb/HIF-1α signaling pathway. Periventricular leukomalacia (PVL), the dominant cerebral white matter injury disease, is induced by hypoxia–ischemia and inflammation in premature infants. The activation of A 2B adenosine receptor (A 2B AR) 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 A 2B AR selective antagonist, greatly ameliorated cerebral ischemic injury by increasing body weights, reducing infarct volume, brain injury, inflammation and contributing to long-term learning memory functional recovery of the PVL mice. Meanwhile, PSB-603 treatment suppressed neurons apoptosis as characterized by reducing of Caspase-3 level, inhibited microglia activation and attenuated hypomyelination through promoting MBP expression and oligodendrocytes differentiation. A 2B AR 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 A 2B AR promoter to induce expression of A 2B AR, was shown to be decreased by PSB-603. Taken together, A 2B AR inhibition can ameliorate hypoxic-ischemic injury in PVL mice maybe through PKC/Erk/Creb/HIF-1α signaling pathway. [ABSTRACT FROM AUTHOR]