Recombinant Human Erythropoietin Augments Neovascularization Responses in a Neonatal Rat Model of Premature Brain Damage by Phosphatidylinositol 3 Kinase/Akt Pathway

Abstract

Background:Recombinant human-erythropoietin (rh-EPO) has therapeutic efficacy for premature infants with brain damage during the active rehabilitation and anti-inflammation. In the present study, we found that the rh-EPO was related to the promotion of neovascularization. Our aim was to investigate whether rh-EPO augments neovascularization in the neonatal rat model of premature brain damage through the phosphatidylinositol 3 kinase (PI3K)/protein kinase B (Akt) signaling pathway.Methods:Postnatal day 5 (PD5), rats underwent permanent ligation of the right common carotid artery and were exposed to hypoxia for 2 h. All the rat pups were randomized into five groups as follows: (1) control group; (2) hypoxia-ischemic (HI) group; (3) HI + LY294002 group; (4) HI + rh-EPO group; and (5) HI + rh-EPO + LY294002 group. The phospho-Akt protein was tested 90 min after the whole operation, and CD34, vascular endothelial growth factor receptor 2 (VEGFR2), and vascular endothelial growth factor (VEGF) were also tested 2 days after the whole operation.Results:In the hypoxic and ischemic zone of the premature rat brain, the rh-EPO induced CD34+ cells to immigrate to the HI brain zone (P < 0.05) and also upregulated the VEGFR2 protein expression (P < 0.05) and VEGF mRNA level (P < 0.05) through the PI3K/Akt (P < 0.05) signaling pathway when compared with other groups.Conclusions:The rh-EPO treatment augments neovascularization responses in the neonatal rat model of premature brain damage through the PI3K/Akt signaling pathway. Besides, the endogenous EPO may exist in the HI zone of rat brain and also has neovascularization function through the PI3K/Akt signaling pathway.

Further Evidence of Neuroprotective Effects of Recombinant Human Erythropoietin and Growth Hormone in Hypoxic Brain Injury in Neonatal Mice

“…In contrast, our brain-region-specific IHC analysis of vascular–endothelial effects of hypoxia found a decreased mean vessel area in the hypoxic parietal cortex and hippocampal areas of developing brains assessed during the subacute and longer-term periods of regeneration after acute hypoxia. These observations are consistent with previous findings that showed transient endothelial upregulation of VEGF in vessels of the SVZ and periventricular and subcortical white matter regions during a 24–48 h post-HI period in the fetal ovine brain [ 44 ] and in neonatal rodent stroke models [ 21 ]. In addition, lower vessel density was also observed in the hypoxic developing piglet brain after a reoxygenation period of 72 h [ 10 ].…”

“…In addition, lower vessel density was also observed in the hypoxic developing piglet brain after a reoxygenation period of 72 h [ 10 ]. Moreover, a slight increase in angiogenesis was found in a neonatal rodent stroke model after 48 h of regeneration [ 21 ] and in our mouse model of acute global brain hypoxia after 72 h of regeneration [ 5 ]. Therefore, different species, hypoxia models, regions of interest, and region-specific regulation may explain variable observations on cerebral VEGF-A regulation and angiogenesis during the post-hypoxic repair period.…”

“…Beyond acute effects, rhEPO enhances longer-term regenerative cerebral processes such as angiogenesis via the PI3K/Akt signaling pathway [ 3 , 19 ] associated with upregulation of VEGF and ANGPTs and increased vessel density in the white matter, hippocampus, and parietal cortex [ 5 , 21 , 22 ]. Moreover, rhEPO increases cerebral protein levels of the TJ protein OCLN in neonatal rodent stroke [ 23 ], ventilation-induced cerebral white matter injury in preterm lambs [ 24 ], and traumatic brain injury [ 25 ], indicating its protective potential against hypoxia-induced BBB disruption.…”

Transcriptome analysis and differentially expressed gene screening for hypoxic-ischemic brain damage in rats treated with acupuncture

“…Hippocampal neurons could be protected against excessive autophagy and apoptosis through the PI3K/Akt signaling pathway 41 . EPO was found to promote cerebrovascular regeneration by activating the PI3K/Akt signaling pathway in premature brain damage 42 . In our results, Cdkn2a, the other target gene of TCONS_00013568, was also related to glioma and the p53 signaling pathway.…”

Sirtuins: Developing Innovative Treatments for Aged-Related Memory Loss and Alzheimer’s Disease

“…Multiple pathways may lead to AD such as cellular injury from βamyloid (Aβ), tau, excitotoxicity, mitochondrial damage, acetylcholine loss, astrocytic cell injury, oxidative stress, mechanistic target of rapamycin, microRNAs, and iron regulation (45,47,(61)(62)(63)(64)(65). Most available treatments that are directed to treat AD involve the use of cholinesterase inhibitors (66) while newer therapies focus on trophic pathways such as erythropoietin (EPO) (61,(67)(68)(69)(70)(71)(72).…”