(559) Synthetic PreImplantation Factor plus hypothermia treatment reverses perinatal hypoxic-ischemic encephalopathy in rats

Perinatal hypoxic-ischemic encephalopathy (HIE) can result in newborn death or long-term neurologic injury. Hypothermia (HPT) reduces mortality and developmental complications from HIE, but 40-50% of infants still die or suffer severe disability. Given synthetic PreImplantation Factor’s (sPIF) neuroprotective effects, we examined the efficacy of sPIF against HIE alone or with HPT. 


Study Design:

Hypoxic ischemic injury (HII) was induced in P7 neonatal Wistar rats using ligation of the left carotid artery and exposure to hypoxia (8% O₂/92% N₂). Rats were subjected to HPT (32.5^oC) for 5 hours post-surgery with or without subcutaneous injection of sPIF (1 mg/kg, twice a day for 7 days post-injury). Acute (7 days after HII, n=12/group) and long-term (42 days after HII, n=6/group) neuronal/glial defects were analyzed by morphological (histopathological, immunofluorescence, & western blots) and neurobehavioral abnormalities (Rota-Rod) post-treatment with sPIF and HPT. Data were subjected to ANOVA and Tukey’s test with a level of significance p < 0.05.

 


Results:

HII induced severe neuronal loss, astrogliosis [increased glial fibrillary acidic protein (GFAP), a marker of astrocytes)], microglial activation (increased Iba1), and cleaved caspase-3 (apoptosis), 7 days post-HII. Treatment with sPIF significantly reduced the effects of HII (p < 0.05), while HPT alone had no effect post-HII (Fig. 1).  sPIF’s effects were augmented by HPT post-HII (p < 0.05) (Fig. 1). In long-term untreated HII rats, we found significant neuronal loss, and defects in motor coordination, while GFAP was significantly decreased, in contrast to acute injury (novel finding). Treatment with sPIF plus HPT significantly reduced HII-induced neuronal loss (Fig. 1), behavioral deficits (Fig. 2), and astrogliosis (Fig. 1).


Conclusion:

sPIF alone or in combination with HPT significantly decreases neuronal damage and improves behavioral deficits in HIE by sustaining glial function. sPIF should be pursued as a therapy for HIE.  This work was supported by NIH/ NICHD R41HD100269.