Abstract:
Periventricular leukomalacia (PVL), the dominant cerebral white matter injury disease, is induced by hypoxia-ischemia and inflammation in premature infants. The activation of A2B adenosine receptor (A2BAR) 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 A2BAR 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. A2BAR 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 A2BAR promoter to induce expression of A2BAR, was shown to be decreased by PSB-603. Taken together, A2BAR inhibition can ameliorate hypoxic-ischemic injury in PVL mice maybe through PKC/Erk/Creb/HIF-1α signaling pathway.
摘要:
脑室周围白质软化(PVL),显性脑白质损伤疾病,是由早产儿缺氧缺血和炎症引起的。A2B腺苷受体(A2BAR)的激活被证明涉及炎症,缺血,和其他典型的应激反应,但其在PVL中的确切功能尚未明确。通过右颈动脉结扎诱导缺氧缺血,然后暴露于缺氧和腹膜内(i.p.)注射脂多糖(LPS),我们从PVL小鼠模型(P9)中获得了初步见解。结果表明,A2BAR选择性拮抗剂PSB-603的治疗,通过增加体重大大改善脑缺血损伤,减少梗死体积,脑损伤,炎症并促进PVL小鼠的长期学习记忆功能恢复。同时,PSB-603治疗抑制神经元凋亡,其特征是Caspase-3水平降低,通过促进MBP表达和少突胶质细胞分化来抑制小胶质细胞的活化和减弱髓鞘形成。A2BAR抑制也增加了PKC的表达,然后探索PKC下游信号分子的活性.与对照组相比,PSB-603治疗组的Erk表达和Creb磷酸化表现出上调。缺氧诱导因子-1α(HIF-1α),缺氧的直接目标,通过与A2BAR启动子结合以诱导A2BAR的表达,这是腺苷信号传导的关键调节剂,显示被PSB-603减少。一起来看,A2BAR抑制可能通过PKC/Erk/Creb/HIF-1α信号通路改善PVL小鼠缺氧缺血性损伤。