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。脑室周围白色物质损伤（PWMI）是早产儿脑损伤的最常见原因，其特征是白色物质丢失和继发性脑室扩大。不幸的是，没有直接预防PWMI的策略。近年来，我们发现腺苷通过A1腺苷受体（A1 ARs）发挥作用，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延迟髓鞘形成有关，如PWMI。重要的是，阻断A1 AR可防止缺氧诱导的脑室扩大和髓鞘形成减少。基于这些观察结果，我们认为，这是可能的，以防止缺氧诱导的脑损伤和PWMI通过阻断腺苷的作用，使用药物治疗。为了开发预防PWMI的新临床策略，我们提出了以下具体目标： SA 1.测试四种不同的方法来阻断腺苷在缺氧中的作用，包括PEG-腺苷脱氨酶，它降解腺苷，是FDA批准的药物;咖啡因，它是一种非特异性腺苷拮抗剂，是FDA批准的药物; 1，3-二丙基-8-环戊基黄嘌呤（DPCPX），这是一种有效的和高度选择性的A1 AR拮抗剂; SCH 58261，这是一种A2 aAR拮抗剂。 SA 2.测试上述方法预防缺氧性脑损伤的有效性。 SA 3.测试抗腺苷治疗在预防缺氧引起的行为障碍中的有效性。预计这些研究将导致直接预防脑损伤的新的和实用的策略。

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.