? ? 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. ? ?
| Rivkees, Scott A; Wendler, Christopher C (2011) Adverse and protective influences of adenosine on the newborn and embryo: implications for preterm white matter injury and embryo protection. Pediatr Res 69:271-8 |
| Akundi, Ravi Shankar; Rivkees, Scott A (2009) Hypoxia alters cell cycle regulatory protein expression and induces premature maturation of oligodendrocyte precursor cells. PLoS One 4:e4739 |
| Back, Stephen A; Craig, Andrew; Luo, Ning Ling et al. (2006) Protective effects of caffeine on chronic hypoxia-induced perinatal white matter injury. Ann Neurol 60:696-705 |
