Critical Shifts in Cerebral White Matter Lipid Profiles After Ischemic-Reperfusion Brain Injury in Fetal Sheep as Demonstrated by the Positive Ion Mode MALDI-Mass Spectrometry.

Abstract

Ischemic-reperfusion (I/R) injury to cerebral white matter during the perinatal period leads to long-term cognitive and motor disabilities in children. Immature white matter oligodendrocytes are especially vulnerable to metabolic insults such as those caused by hypoxic, ischemic, and reperfusion injury. Consequences include an impaired capacity of oligodendrocytes to generate and maintain mature lipid-rich myelin needed for efficient neuronal conductivity. Further research is needed to increase an understanding of the early, possibly reversible myelin-associated pathologies that accompany I/R white matter injury. This experiment characterized I/R time-dependent alterations in cerebral white matter lipid profiles in an established fetal sheep model. Fetal sheep (127 days gestation) were subjected to 30 min of bilateral carotid artery occlusion followed by 4 h (n = 5), 24 h (n = 7), 48 h (n = 3), or 72 h (n = 5) of reperfusion, or sham treatment (n = 5). Supraventricular cerebral white matter lipids were analyzed using the positive ionization mode matrix-assisted laser desorption/ionization mass spectrometry. Striking I/R-associated shifts in phospholipid (PL) and sphingolipid expression with a prominent upregulation of cardiolipin, phosphatidylcholine, phosphatidylinositol monomannoside, sphingomyelin, sulfatide, and ambiguous or unidentified lipids were observed to occur mainly at I/R-48 and normalized or suppressed responses at I/R-72. In fetal sheep, cerebral I/R caused major shifts in white matter myelin lipid composition favoring the upregulated expression of diverse PLs and sphingolipids which are needed to support neuronal membrane, synaptic, metabolic, and cell signaling functions.