Anti-Adenosine Therapy of Neonatal Brain Injury

描述(由申请人提供)： 5%到10%的早产儿会遭受严重的神经损伤。脑室周围白质损伤(PWMI)是目前早产儿脑损伤最常见的原因，其特征是脑白质丢失和继发性脑室扩大。不幸的是，没有旨在直接预防PWMI的战略。最近我们发现腺苷通过A1腺苷受体(A1ARs)在PWMI的发病机制中发挥重要作用。我们发现，低氧饲养与少突胶质细胞的异常成熟和髓鞘形成延迟有关，就像PWMI一样。重要的是，阻断A1受体可以防止缺氧引起的脑室增大和髓鞘形成减少。基于这些观察，我们认为可以通过药物治疗阻断腺苷的作用来预防缺氧性脑损伤和PWMI。为了开发预防PWMI的新临床策略，我们提出了以下具体目标： SA1.测试四种不同的方法阻断腺苷在缺氧时的作用，包括降解腺苷的聚乙二醇腺苷脱氨酶，是FDA批准的药物；咖啡因，非特异性腺苷拮抗剂，FDA批准的药物；1，3-二丙基-8-环戊基黄嘌呤(DPCPX)，有效和高选择性的A1AR拮抗剂；SCH58261，A2aAR拮抗剂。 SA2.检测上述方法在预防缺氧性脑损伤中的有效性。 SA3.测试抗腺苷治疗在预防缺氧性行为障碍方面的有效性。预计这些研究将导致直接预防脑损伤的新颖和实用的策略。

DESCRIPTION (provided by applicant): Five to ten percent of premature infants will sustain significant neurological injuries. Periventricular white matter injury (PWMI) is now the most common cause of brain injury in preterm infants and is characterized by a loss of white matter and secondary ventricular enlargement. Unfortunately, strategies aimed at directly preventing PWMI are not available. Recently we discovered that adenosine, acting through A1 adenosine receptors (A1ARs), plays a major role in the pathogenesis of PWMI. We find that hypoxic rearing is associated with abnormal maturation of oligodendrocytes and delayed myelination, as in PWMI. Importantly, blockade of A1 ARs prevents hypoxia-induced ventriculomegaly and reduced myelination. Based on these observations we believe that it is possible to prevent hypoxia-induced brain injury and PWMI by blocking adenosine action using drug therapy. To develop a new clinical strategy for PWMI prevention, we propose the following Specific Aims: SA1. Test four different approaches for blocking adenosine action in hypoxia, including PEG-adenosine deaminase, which degrades adenosine and is an FDA approved drug; caffeine, which is a non-specific adenosine antagonist and is an FDA approved drug; 1,3-dipropyl-8-cyclopentylxanthine (DPCPX), which is a potent and highly selective A1AR antagonist; SCH58261, which is an A2aAR antagonist. SA2. Test the effectiveness of the above approaches in preventing hypoxia-induced brain injury. SA3. Test the effectiveness of anti-adenosine therapy in preventing hypoxia-induced behavior disturbances. It is anticipated that these studies will lead to novel and practical strategies for directly preventing brain injury.