Overweight worsens apoptosis,neuroinflammation and blood-brain barrier damage after hypoxic ischemia in neonatal brain through JNK hyperactivation

Background: apoptosis,neuroinflammation and blood-brain barrier (bbb) damage affect the susceptibility of the developing brain to hypoxic-ischemic (hi) insults. c-jun n-terminal kinase (jnk) is an important mediator of insulin resistance in obesity. we hypothesized that neonatal overweight aggravates hi brain damage through jnk hyperactivation-mediated upregulation of neuronal apoptosis,neuroinflammation and bbb leakage in rat pups.methods: overweight (of) pups were established by reducing the litter size to 6,and control (nf) pups by keeping the litter size at 12 from postnatal (p) day 1 before hi on p7. immunohistochemistry and immunoblotting were used to determine the tunel-(+) cells and bbb damage,cleaved caspase-3 and poly (adp-ribose) polymerase (parp),and phospho-jnk and phospho-bimellevels. immunofluorescence was performed to determine the cellular distribution of phospho-jnk.results: compared with nf pups,of pups had a significantly heavier body-weight and greater fat deposition on p7. compared with the nf-hi group,the of-hi group showed significant increases of tunel-(+) cells,cleaved levels of caspase-3 and parp,and ed1-(+) activated microglia and bbb damage in the cortex 24 hours post-hi. immunofluorescence of the of-hi pups showed that activated-caspase 3 expression was found mainly in neun-(+) neurons and reca1-(+) vascular endothelial cells 24 hours post-hi. the of-hi group also had prolonged escape latency in the morris water maze test and greater brain-volume loss compared with the nf-hi group when assessed at adulthood. phospho-jnk and phospho-bimellevels were higher in of-hi pups than in nf-hi pups immediately post-hi. jnk activation in of-hi pups was mainly expressed in neurons,microglia and vascular endothelial cells. inhibiting jnk activity by as601245 caused more attenuation of cleaved caspase-3 and parp,a greater reduction of microglial activation and bbb damage post-hi,and significantly reduced brain damage in of-hi than in nf-hi pups.conclusions: neonatal overweight increased hi-induced neuronal apoptosis,microglial activation and bbb damage,and aggravated hi brain damage in rat pups through jnk hyperactivation. © 2011 tu et al; licensee biomed central ltd.