II-PTB results in a spectrum of adverse neurobehavioral disorders. Using a murine model of II-PTB, we have demonstrated a marked elevation of IL1β in the fetal brain and fetal neuronal injury. As IL1β is a key mediator in pathogenesis of many neuroinflammatory disorders, we hypothesized that maternal pretreatment with IL1β antagonist (Kineret; ILA) would prevent neonatal brain injury associated with II-PTB.
A mouse model of II-PTB was used. ILA was injected IP at 10 mg/kg into CD-1 dams 30min prior to IU injections of lipopolysaccharide (LPS) or normal saline (NS). There were 3 groups: 1) IP NS+IU NS (control; n=10 dams); 2) IP NS+IU LPS (LPS; n=20 dams); 3)IP ILA+IU LPS (ILA; n=13 dams). Rates of PTB, neonatal morbidity and mortality, growth and neurological development were evaluated. Gene expression was evaluated in the neonatal brain (NB) at PND5 in a brain region specific manner using QPCR. We assessed neuronal and neurobehavioral specific markers: nNOS, NMDAR1, synaptobrevin, synaptophysin, synaptogyrin, doublecourtin, reelin and neurexin; markers of astrocytes GFAP and oligodendrocytes PLP1. Specific protein changes were assessed with Western blot (WB). For QPCR and WB, 3-5 litters/group (with 3 NB per litter) were compared.
ILA was not able to prevent II-PTB (p>0.05). Postnatal growth in ILA group was not different from control (p>0.05). Pretreatment with ILA resulted in postnatal levels of neuronal and neurobehavioral markers in cortex comparable to those of control (p>0.05). However, cerebellar levels of reelin, neurexin, NMDAR1, synaptobrevin and nNOS in NB remained to be elevated as compared to control (p<0.05).
Maternally administered ILA, prior to intrauterine inflammation, appears to prevent neonatal brain injury in a region specific manner. The results indicate that fetal brain injury in II-PTB occurs by different mechanisms in fetal cortex and cerebellum. Moreover, these studies provide evidence that fetal brain injury and preterm birth, in response to intrauterine inflammation, may involve divergent pathways. (Funded by ABOG/AAOGF)
© 2012 Mosby, Inc. Published by Elsevier Inc. All rights reserved.