JNK signaling is the shared pathway linking neuroinflammation,blood-brain barrier disruption,and oligodendroglial apoptosis in the white matter injury of the immature brain

Background: white matter injury is the major form of brain damage in very preterm infants. selective white matter injury in the immature brain can be induced by lipopolysaccharide (lps)-sensitized hypoxic-ischemia (hi) in the postpartum (p) day 2 rat pups whose brain maturation status is equivalent to that in preterm infants less than 30 weeks of gestation. neuroinflammation,blood-brain barrier (bbb) damage and oligodendrocyte progenitor apoptosis may affect the susceptibility of lps-sensitized hi in white matter injury. c-jun n-terminal kinases (jnk) are important stress-responsive kinases in various forms of insults. we hypothesized that lps-sensitized hi causes white matter injury through jnk activation-mediated neuroinflammation,bbb leakage and oligodendroglial apoptosis in the white matter of p2 rat pups.methods: p2 pups received lps (0.05 mg/kg) or normal saline injection followed by 90-min hi. immunohistochemistry and immunoblotting were used to determine microglia activation,tnf-α,bbb damage,cleaved caspase-3,jnk and phospho-jnk (p-jnk),myelin basic protein (mbp),and glial fibrillary acidic protein (gfap) expression. immunofluorescence was performed to determine the cellular distribution of p-jnk. pharmacological and genetic approaches were used to inhibit jnk activity.results: p2 pups had selective white matter injury associated with upregulation of activated microglia,tnf-α,igg extravasation and oligodendroglial progenitor apoptosis after lps-sensitized hi. immunohistochemical analyses showed early and sustained jnk activation in the white matter at 6 and 24 h post-insult. immunofluorescence demonstrated upregulation of p-jnk in activated microglia,vascular endothelial cells and oligodendrocyte progenitors,and also showed perivascular aggregation of p-jnk-positive cells around the vessels 24 h post-insult. jnk inhibition by as601245 or by antisense oligodeoxynucleotides (odn) significantly reduced microglial activation,tnf-α immunoreactivity,igg extravasation,and cleaved caspase-3 in the endothelial cells and oligodendrocyte progenitors,and also attenuated perivascular aggregation of p-jnk-positive cells 24 h post-insult. the as601245 or jnk antisense odn group had significantly increased mbp and decreased gfap expression in the white matter on p11 than the vehicle or scrambled odn group.conclusions: lps-sensitized hi causes white matter injury through jnk activation-mediated upregulation of neuroinflammation,bbb leakage and oligodendrocyte progenitor apoptosis in the immature brain. © 2012 wang et al.; licensee biomed central ltd.