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

Ann Neurol. 2006 Dec;60(6):696-705. doi: 10.1002/ana.21008.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine / antagonists & inhibitors
  • Adenosine / metabolism
  • Adenosine A1 Receptor Antagonists
  • Animals
  • Animals, Newborn
  • Asphyxia Neonatorum / drug therapy*
  • Asphyxia Neonatorum / pathology
  • Asphyxia Neonatorum / physiopathology
  • Brain / drug effects
  • Brain / pathology
  • Brain / physiopathology
  • Caffeine / pharmacology*
  • Caffeine / therapeutic use
  • Cell Differentiation / drug effects
  • Cell Differentiation / physiology
  • Cell Lineage / drug effects
  • Cell Lineage / physiology
  • Chronic Disease
  • Disease Models, Animal
  • Female
  • Humans
  • Hypoxia, Brain / drug therapy*
  • Hypoxia, Brain / pathology
  • Hypoxia, Brain / physiopathology
  • Infant, Newborn
  • Leukomalacia, Periventricular / drug therapy*
  • Leukomalacia, Periventricular / pathology
  • Leukomalacia, Periventricular / physiopathology
  • Mice
  • Mice, Inbred C57BL
  • Nerve Fibers, Myelinated / drug effects
  • Nerve Fibers, Myelinated / pathology
  • Neuroprotective Agents / pharmacology*
  • Neuroprotective Agents / therapeutic use
  • Oligodendroglia / drug effects
  • Oligodendroglia / metabolism
  • Oligodendroglia / pathology
  • Pregnancy
  • Receptor, Adenosine A1 / metabolism
  • Stem Cells / drug effects
  • Stem Cells / metabolism


  • Adenosine A1 Receptor Antagonists
  • Neuroprotective Agents
  • Receptor, Adenosine A1
  • Caffeine
  • Adenosine