Perinatal hypoxic-ischemic reperfusion (I/R)-related
brain injury is a leading cause of neurologic morbidity and life-long disability in children. Infants exposed to I/R
brain injury develop long-term cognitive and behavioral deficits, placing a large burden on parents and society. Therapeutic strategies are currently not available for infants with I/R brain damage, except for
hypothermia, which can only be used in full term infants with
hypoxic-ischemic encephalopathy (HIE). Moreover,
hypothermia is only partially protective. Pro-inflammatory
cytokines are key contributors to the pathogenesis of perinatal I/R
brain injury. Interleukin-1β (IL-1β) is a critical pro-inflammatory
cytokine, which has been shown to predict the severity of HIE in infants. We have previously shown that systemic infusions of mouse anti-ovine IL-1β
monoclonal antibody (mAb) into fetal sheep resulted in anti-IL-1β mAb penetration into brain, reduced I/R-related increases in IL-1β expression and blood-brain barrier (BBB) dysfunction in fetal brain. The purpose of the current study was to examine the effects of systemic infusions of anti-IL-1β mAb on short-term I/R-related parenchymal
brain injury in the fetus by examining: 1) histopathological changes, 2) apoptosis and
caspase-3 activity, 3) neuronal degeneration 4) reactive
gliosis and 5)
myelin basic protein (MBP) immunohistochemical staining. The study groups included non-ischemic controls, placebo-treated ischemic, and anti-IL-1β mAb treated ischemic fetal sheep at 127days of gestation. The systemic
intravenous infusions of anti-IL-1β mAb were administered at fifteen minutes and four hours after in utero
brain ischemia. The duration of each infusion was two hours. Parenchymal
brain injury was evaluated by determining pathological injury scores, ApopTag® positive cells/mm2,
caspase-3 activity,
Fluoro-Jade B positive cells/mm2,
glial fibrillary acidic protein (GFAP) and MBP staining in the brains of fetal sheep 24h after 30min of
ischemia. Treatment with anti-IL-1β mAb reduced (P<0.05) the global pathological injury scores, number of apoptotic positive cells/mm2, and
caspase-3 activity after
ischemia in fetal sheep. The regional pathological scores and
Fluoro-Jade B positive cells/mm2 did not differ between the placebo- and anti-IL-1β mAb treated ischemic fetal sheep. The percent of the cortical area stained for GFAP was lower (P<0.05) in the placebo ischemic treated than in the non-ischemic group, but did not differ between the placebo- and anti-IL-1β mAb treated ischemic groups. MBP immunohistochemical expression did not differ among the groups. In conclusion, infusions of anti-IL-1β mAb attenuate short-term I/R-related histopathological tissue injury, apoptosis, and reduce I/R-related increases in
caspase-3 activity in ovine fetal brain. Therefore, systemic infusions of anti-IL-1β mAb attenuate short-term I/R-related parenchymal
brain injury in the fetus.