Brief exposure to hyperoxia depletes the glial progenitor pool and impairs functional recovery after hypoxic-ischemic brain injury.
Patterns of hypoxic-ischemic brain injury in infants and children suggest vulnerability in regions of white matter development, and injured patients develop defects in myelination resulting in cerebral palsy and motor deficits. Reperfusion exacerbates the oxidative stress that occurs after such injuries and may impair recovery. Resuscitation after hypoxic-ischemic injury is routinely performed using 100% oxygen, and this practice may increase the oxidative stress that occurs during reperfusion and further damage an already compromised brain. We show that brief exposure (30 mins) to 100% oxygen during reperfusion worsens the histologic injury in young mice after unilateral brain hypoxia-ischemia, causes an accumulation of the oxidative metabolite nitrotyrosine, and depletes preoligodendrocyte glial progenitors present in the cortex. This damage can be reversed with administration of the antioxidant ebselen, a glutathione peroxidase mimetic. Moreover, mice recovered in 100% oxygen have a more disrupted pattern of myelination and develop a static motor deficit that mimics cerebral palsy and manifests itself by significantly worse performance on wire hang and rotorod motor testing. We conclude that exposure to 100% oxygen during reperfusion after hypoxic-ischemic brain injury increases secondary neural injury, depletes developing glial progenitors, interferes with myelination, and ultimately impairs functional recovery.
Koch
Joshua D
JD
Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
Miles
Darryl K
DK
Gilley
Jennifer A
JA
Yang
Cui-Ping
CP
Kernie
Steven G
SG
D000818:Animals; D002540:Cerebral Cortex / Q000473:pathology; D003711:Demyelinating Diseases / Q000209:etiology; D018496:Hyperoxia / Q000150:complications*; D020925:Hypoxia-Ischemia, Brain; D051379:Mice; D009457:Neuroglia / Q000473:pathology*; D010100:Oxygen / Q000008:administration & dosage / Q000009:adverse effects; D020127:Recovery of Function; D013234:Stem Cells / Q000473:pathology*
D010100:Oxygen