Neonatal
hypoxic ischemic encephalopathy (HIE) resulting from intrapartum
asphyxia is a global problem that causes severe disabilities and up to 1 million deaths annually. A variant form of activated
protein C, 3K3A-APC, has cytoprotective properties that attenuate
brain injury in models of adult
stroke. In this study, we compared the ability of 3K3A-APC and APC (wild-type (wt)) to attenuate neonatal
brain injury, using the spiny mouse (Acomys cahirinus) model of intrapartum
asphyxia. Pups were delivered at 38 days of gestation (term = 39 days), with an intrapartum hypoxic insult of 7.5 min (intrapartum
asphyxia cohort), or immediate removal from the uterus (control cohort). After 1 h, pups received a
subcutaneous injection of 3K3A-APC or wild-type APC (wtAPC) at 7 mg/kg, or vehicle (saline). At 24 h of age, pups were killed and brain tissue was collected for measurement of
inflammation and cell death using RT-qPCR and histopathology. Intrapartum
asphyxia increased
weight loss,
inflammation, and apoptosis/
necrosis in the newborn brain. 3K3A-APC administration maintained
body weight and ameliorated an
asphyxia-induced increase of TGFβ1
messenger RNA expression in the cerebral cortex, immune cell aggregation in the corpus callosum, and cell death in the deep gray matter and hippocampus. In the cortex, 3K3A-APC appeared to exacerbate the immune response to the hypoxic ischemic insult. While wtAPC reduced cell death in the corpus callosum and hippocampus following intrapartum
asphyxia, it increased markers of neuro-
inflammation and cell death in control pups. These findings suggest 3K3A-APC administration may be a useful
therapy to reduce cell death and neonatal
brain injury associated with HIE.