Synergistic Effect in Neurological Recovery via Anti-Apoptotic Akt Signaling in Umbilical Cord Blood and Erythropoietin Combination Therapy for Neonatal Hypoxic-Ischemic Brain Injury

Our previous clinical studies demonstrated the synergistic therapeutic effect induced by co-administering recombinant human erythropoietin (rhEPO) in human umbilical cord blood (hUCB) therapy for children with cerebral palsy. However, the cellular mechanism beyond the beneficial effects in this comb...

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Autores principales:	Jee In Choi, Joo-Wan Choi, Kyu-Ho Shim, Jin Seung Choung, Hyun-Jin Kim, Hye Ryeong Sim, Mi Ri Suh, Joo Eun Jung, MinYoung Kim
Formato:	article
Lenguaje:	EN
Publicado:	MDPI AG 2021
Materias:	cord blood cell therapy erythropoietin hypoxic–ischemic brain injury neurobehavioral recovery anti-apoptosis Akt signaling pathway Biology (General) QH301-705.5 Chemistry QD1-999
Acceso en línea:	https://doaj.org/article/94f14bb0dc75484aab8d9060857bcb7f
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spelling	oai:doaj.org-article:94f14bb0dc75484aab8d9060857bcb7f2021-11-11T17:25:26ZSynergistic Effect in Neurological Recovery via Anti-Apoptotic Akt Signaling in Umbilical Cord Blood and Erythropoietin Combination Therapy for Neonatal Hypoxic-Ischemic Brain Injury10.3390/ijms2221119951422-00671661-6596https://doaj.org/article/94f14bb0dc75484aab8d9060857bcb7f2021-11-01T00:00:00Zhttps://www.mdpi.com/1422-0067/22/21/11995https://doaj.org/toc/1661-6596https://doaj.org/toc/1422-0067Our previous clinical studies demonstrated the synergistic therapeutic effect induced by co-administering recombinant human erythropoietin (rhEPO) in human umbilical cord blood (hUCB) therapy for children with cerebral palsy. However, the cellular mechanism beyond the beneficial effects in this combination therapy still needs to be elucidated. A hypoxic–ischemic encephalopathy (HIE) model of neonates, representing cerebral palsy, was prepared and randomly divided into five groups (hUCB+rhEPO combination, hUCB, and rhEPO treatments over HIE, HIE control, and sham). Seven days after, hUCB was administered intraperitoneally and the rhEPO injections were started. Neurobehavioral tests showed the best outcome in the combination therapy group, while the hUCB and rhEPO alone treatments also showed better outcomes compared with the control (<i>p</i> < 0.05). Inflammatory cytokines were downregulated by the treatments and attenuated most by the combination therapy (<i>p</i> < 0.05). The hUCB+rhEPO treatment also showed remarkable increase in phosphorylation of Akt and potentiation of anti-apoptotic responses with decreased Bax and increased Bcl-2 (<i>p</i> < 0.05). Pre-treatment of MK-2206, an Akt inhibitor, for the combination therapy depressed the anti-apoptotic effects. In conclusion, these findings suggest that the therapeutic effect of hUCB therapy might be potentiated by co-administration of rhEPO via augmentation of anti-inflammatory and anti-apoptotic responses related to the phosphorylation of Akt.Jee In ChoiJoo-Wan ChoiKyu-Ho ShimJin Seung ChoungHyun-Jin KimHye Ryeong SimMi Ri SuhJoo Eun JungMinYoung KimMDPI AGarticlecord blood cell therapyerythropoietinhypoxic–ischemic brain injuryneurobehavioral recoveryanti-apoptosisAkt signaling pathwayBiology (General)QH301-705.5ChemistryQD1-999ENInternational Journal of Molecular Sciences, Vol 22, Iss 11995, p 11995 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	cord blood cell therapy erythropoietin hypoxic–ischemic brain injury neurobehavioral recovery anti-apoptosis Akt signaling pathway Biology (General) QH301-705.5 Chemistry QD1-999
spellingShingle	cord blood cell therapy erythropoietin hypoxic–ischemic brain injury neurobehavioral recovery anti-apoptosis Akt signaling pathway Biology (General) QH301-705.5 Chemistry QD1-999 Jee In Choi Joo-Wan Choi Kyu-Ho Shim Jin Seung Choung Hyun-Jin Kim Hye Ryeong Sim Mi Ri Suh Joo Eun Jung MinYoung Kim Synergistic Effect in Neurological Recovery via Anti-Apoptotic Akt Signaling in Umbilical Cord Blood and Erythropoietin Combination Therapy for Neonatal Hypoxic-Ischemic Brain Injury
description	Our previous clinical studies demonstrated the synergistic therapeutic effect induced by co-administering recombinant human erythropoietin (rhEPO) in human umbilical cord blood (hUCB) therapy for children with cerebral palsy. However, the cellular mechanism beyond the beneficial effects in this combination therapy still needs to be elucidated. A hypoxic–ischemic encephalopathy (HIE) model of neonates, representing cerebral palsy, was prepared and randomly divided into five groups (hUCB+rhEPO combination, hUCB, and rhEPO treatments over HIE, HIE control, and sham). Seven days after, hUCB was administered intraperitoneally and the rhEPO injections were started. Neurobehavioral tests showed the best outcome in the combination therapy group, while the hUCB and rhEPO alone treatments also showed better outcomes compared with the control (<i>p</i> < 0.05). Inflammatory cytokines were downregulated by the treatments and attenuated most by the combination therapy (<i>p</i> < 0.05). The hUCB+rhEPO treatment also showed remarkable increase in phosphorylation of Akt and potentiation of anti-apoptotic responses with decreased Bax and increased Bcl-2 (<i>p</i> < 0.05). Pre-treatment of MK-2206, an Akt inhibitor, for the combination therapy depressed the anti-apoptotic effects. In conclusion, these findings suggest that the therapeutic effect of hUCB therapy might be potentiated by co-administration of rhEPO via augmentation of anti-inflammatory and anti-apoptotic responses related to the phosphorylation of Akt.
format	article
author	Jee In Choi Joo-Wan Choi Kyu-Ho Shim Jin Seung Choung Hyun-Jin Kim Hye Ryeong Sim Mi Ri Suh Joo Eun Jung MinYoung Kim
author_facet	Jee In Choi Joo-Wan Choi Kyu-Ho Shim Jin Seung Choung Hyun-Jin Kim Hye Ryeong Sim Mi Ri Suh Joo Eun Jung MinYoung Kim
author_sort	Jee In Choi
title	Synergistic Effect in Neurological Recovery via Anti-Apoptotic Akt Signaling in Umbilical Cord Blood and Erythropoietin Combination Therapy for Neonatal Hypoxic-Ischemic Brain Injury
title_short	Synergistic Effect in Neurological Recovery via Anti-Apoptotic Akt Signaling in Umbilical Cord Blood and Erythropoietin Combination Therapy for Neonatal Hypoxic-Ischemic Brain Injury
title_full	Synergistic Effect in Neurological Recovery via Anti-Apoptotic Akt Signaling in Umbilical Cord Blood and Erythropoietin Combination Therapy for Neonatal Hypoxic-Ischemic Brain Injury
title_fullStr	Synergistic Effect in Neurological Recovery via Anti-Apoptotic Akt Signaling in Umbilical Cord Blood and Erythropoietin Combination Therapy for Neonatal Hypoxic-Ischemic Brain Injury
title_full_unstemmed	Synergistic Effect in Neurological Recovery via Anti-Apoptotic Akt Signaling in Umbilical Cord Blood and Erythropoietin Combination Therapy for Neonatal Hypoxic-Ischemic Brain Injury
title_sort	synergistic effect in neurological recovery via anti-apoptotic akt signaling in umbilical cord blood and erythropoietin combination therapy for neonatal hypoxic-ischemic brain injury
publisher	MDPI AG
publishDate	2021
url	https://doaj.org/article/94f14bb0dc75484aab8d9060857bcb7f
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Synergistic Effect in Neurological Recovery via Anti-Apoptotic Akt Signaling in Umbilical Cord Blood and Erythropoietin Combination Therapy for Neonatal Hypoxic-Ischemic Brain Injury

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