Protective effects of caffeine on chronic hypoxia‐induced perinatal white matter injury

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Abstract
Objective Periventricular white matter injury (PWMI) is the major cause of cerebral palsy and cognitive impairment in prematurely born infants. PWMI is characterized by reductions in cerebral myelination and cerebrocortical volumes and is associated with secondary ventriculomegaly. In neonatal rodents, these features of PWMI can be induced by rearing in chronic hypoxia or by activation of A1 adenosine receptors. We determined: (1) whether altered maturation or development of one or more oligodendrocyte (OL) lineage stages plays a role in the pathogenesis of the myelination disturbances associated with exposure to chronic hypoxia, and (2) whether blockade of A1 adenosine receptor action with the adenosine antagonist caffeine can prevent hypoxia‐induced white matter injury. Methods Ventriculomegaly and reduced cerebral myelination were generated in mice reared in hypoxia (10% oxygen) from postnatal days 3 (P3) through 12. Results Hypomyelination was related to abnormal OL lineage progression and a reduction in the OL progenitor pool. Myelination was enhanced and ventriculomegaly reduced in hypoxia‐exposed neonatal pups treated with caffeine from P3 to P12. Interpretation These observations support that hypoxia inhibits OL maturation and that caffeine administration during early postnatal development may have utility in the prevention of PWMI. Ann Neurol 2006