Cerebral hypoxia-ischemia during the perinatal period is the single most important cause of acute mortality and chronic disability in newborns, making the enormous physical and emotional strain that is placed on these individuals and their families a life long encumbrance. Despite the best efforts of the research community, an effective clinical therapy has yet to be established. Recently, erythropoietin (EPO) has been shown to be neuroprotective in both experimental and clinical studies. In a neonatal hypoxia-ischemia rat model, we have previously shown that the administration of exogenous recombinant human EPO (rhEPO) before and after the insult was able to preserve brain morphology and brain weight through an inhibition of apoptosis, possibly via an upregulation of HSP-27. Therefore, The objective of this proposal is to determine the mechanisms of neuroprotection by exogenous rhEPO treatment administered after a hypoxic-ischemic insult. The central hypothesis of this proposal is that exogenous rhEPO treatment will protect the brain against apoptosis, neuroinflammation, and the activition of matrix metalloproteinases (MMP). The rationale for the proposed research is that identifying the neuroprotective potential of rhEPO treatment and the mechanisms involved may provide a basis for extending the clinical application to infants suffering hypoxic- ischemic brain damage in the perinatal period. We will address three specific aims to test our central hypothesis.
In Specific aim 1 we will examine the hypothesis that rhEPO will inhibit the apoptotic cascade via the upregulation of HSP70 and HSP27, thereby leading to a reduction in cell death, which translates into an improved neurological and behavioral outcome.
In Specific aim 2, we will examine the hypothesis that rhEPO will decrease the neuroinflammatory response that follows the insult.
In Specific aim 3, we will examine the hypothesis that rhEPO will induce the expression of tissue inhibitors of metalloproteinases (TIMP)-1 and TIMP-2, which will decrease the activity of MMP-9 and MMP-2, respectively, thereby decreasing the disruption of the blood-brain barrier (BBB) and decreasing edema. An established neonatal hypoxia-ischemia model will be used in all these studies. We expect these proposed aims to demonstrate that rhEPO acts at multiple points in the pathological cascade of a hypoxic-ischemic insult and this combination of actions ultimately leads to the reduction of brain injury.
|Shi, Xudan; Doycheva, Desislava Met; Xu, Liang et al. (2016) Sestrin2 induced by hypoxia inducible factor1 alpha protects the blood-brain barrier via inhibiting VEGF after severe hypoxic-ischemic injury in neonatal rats. Neurobiol Dis 95:111-21|
|Lekic, Tim; Klebe, Damon; Poblete, Roy et al. (2015) Neonatal brain hemorrhage (NBH) of prematurity: translational mechanisms of the vascular-neural network. Curr Med Chem 22:1214-38|
|Klebe, Damon; Krafft, Paul R; Hoffmann, Clotilde et al. (2014) Acute and delayed deferoxamine treatment attenuates long-term sequelae after germinal matrix hemorrhage in neonatal rats. Stroke 45:2475-9|
|Fathali, Nancy; Ostrowski, Robert P; Hasegawa, Yu et al. (2013) Splenic immune cells in experimental neonatal hypoxia-ischemia. Transl Stroke Res 4:208-19|
|Burchell, Sherrefa R; Dixon, Brandon J; Tang, Jiping et al. (2013) Isoflurane provides neuroprotection in neonatal hypoxic ischemic brain injury. J Investig Med 61:1078-83|
|Lekic, Tim; Rolland, William; Manaenko, Anatol et al. (2013) Evaluation of the hematoma consequences, neurobehavioral profiles, and histopathology in a rat model of pontine hemorrhage. J Neurosurg 118:465-77|
|Hasegawa, Yu; Suzuki, Hidenori; Altay, Orhan et al. (2013) Role of the sphingosine metabolism pathway on neurons against experimental cerebral ischemia in rats. Transl Stroke Res 4:524-32|
|Charles, MÃ©lissa S; Ostrowski, Robert P; Manaenko, Anatol et al. (2012) Role of the pituitaryâ€“adrenal axis in granulocyte-colony stimulating factor-induced neuroprotection against hypoxiaâ€“ischemia in neonatal rats. Neurobiol Dis 47:29-37|
|Lekic, Tim; Manaenko, Anatol; Rolland, William et al. (2012) Rodent neonatal germinal matrix hemorrhage mimics the human brain injury, neurological consequences, and post-hemorrhagic hydrocephalus. Exp Neurol 236:69-78|
|Fujii, Mutsumi; Duris, Kamil; Altay, Orhan et al. (2012) Inhibition of Rho kinase by hydroxyfasudil attenuates brain edema after subarachnoid hemorrhage in rats. Neurochem Int 60:327-33|
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