Mechanisms of Erythropoietin-induced Neuroprotection in: in-vivo and in-vitro Models of hypoxia Ischema

Abstract

Hypoxic ischemic brain injury (HIBI) is a common cause of neonatal mortality and morbidity. Approximately 60 % of preterm babies and 2% of full term infants suffer from asphyxia. Asphyxia related death accounts for approximately 23% of neonatal mortality annually. Many therapeutic interventions show promise in the laboratory but fail in clinics. A thorough understanding of mechanisms by which promising therapeutic intervention confers its neuroprotection is necessary to promote smoother transitions from bench to the bedside. Erythropoietin (EPO), a hematopoietic growth factor that increases oxygen availability during hypoxia/ischemia is associated with cell survival and neuroprotection in: in vivo and in vitro models of hypoxia ischemia. However these studies hold limited clinical translations because the underlying mechanism remains unclear and the key molecules involved in EPO-induced neuroprotection are still to be determined. Thus the central aim of this proposal is: to determine the key mediators of EPO-induced neuroprotection and the mechanisms by which this occurs in: in vitro and in vivo models of hypoxia ischemia. Two alternate pathways of EPO-induced neuroprotection were elucidated in vitro using oxygen and glucose deprivation to mimic hypoxia ischemia. Our findings showed that EPO treatment resulted in an upregulation of tissues inhibitor of matrix metalloproteinase (TIMP)-1 and inhibition of hypoxia inducible factor (HIF-1α) both of which subsequently decreased in matrix metalloproteinase (MMP)-9 and promoted neuroprotection. MMP-9 inhibition was associated with neuroprotection in both pathways thus, inferring that inhibition of MMP-9 is one of the primary mechanisms of EPO-induced neuroprotection. We also observed that EPO-induced neuroprotection was reversed by inhibition of TIMP-1 or prolyl hydroxylase (PHD)-2. This lends to the conclusion that TIMP-1 and PHD-2 are the key mediators of EPO-induced neuroprotection in: in vivo and in vitro models of hypoxia ischemia