Evaluation of 3K3A-Activated Protein C to Treat Neonatal Hypoxic Ischemic Brain Injury in the Spiny Mouse

Abstract

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.

Midkine: The Who, What, Where, and When of a Promising Neurotrophic Therapy for Perinatal Brain Injury

“…In vivo testing is always the key, but given the multitude of cell and developmentally regulated effects of MK, it seems to have even greater importance to prove the validity of MK as a potential therapeutic. It will also be important to understand the roles of MK in animal models of development and injury, which incorporate the maternal-placental-fetal unit, such as the precocial spiny mouse (236,237), or fetal and newborn sheep (165,238). Current data predominantly comes from altricial species but given the high levels of MK in the amniotic fluid, there is the possibility that preterm birth causes an MK deficiency, and the effect of prematurity and brain injury in these infants warrants attention.…”

Factor VII, EPCR, aPC Modulators: novel treatment for neuroinflammation

“…In recent years there has been a major effort to develop compounds that increase aPC activity, to treat neuroinflammation [ 33 , 34 ]. In the present study, we used novel molecules, which were specifically designed to modify the FVIIa-aPC-EPCR pathway, to achieve an elevation in aPC activity, a lowering of thrombin activity, and a reduction in microglial proliferation.…”