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

• Published in: International journal of molecular sciences 2021-11, Vol.22 (21), p.11995
• Main Authors: Choi, Jee In, Choi, Joo-Wan, Shim, Kyu-Ho, Choung, Jin Seung, Kim, Hyun-Jin, Sim, Hye Ryeong, Suh, Mi Ri, Jung, Joo Eun, Kim, MinYoung
• Format: Article
• Language: English
• Subjects: AKT protein; Angiogenesis; Animals; Animals, Newborn; Apoptosis; Apoptosis - drug effects; Apoptosis - physiology; Bcl-2 protein; Blood; Brain damage; Brain Injuries - metabolism; Brain Injuries - pathology; Brain Injuries - therapy; Brain injury; Brain research; Brain-derived neurotrophic factor; Cerebral palsy; Combination therapy; Cord blood; Cytokines; Disease Models, Animal; Encephalopathy; Erythropoietin; Erythropoietin - pharmacology; Female; Fetal Blood - transplantation; Gene expression; Hypoxia; Hypoxia-Ischemia, Brain - metabolism; Hypoxia-Ischemia, Brain - pathology; Hypoxia-Ischemia, Brain - therapy; Inflammation; Investigations; Ischemia; Kinases; Male; Mice; Mice, Inbred ICR; Neonates; Neurogenesis; Paralysis; Phosphorylation; Proto-Oncogene Proteins c-akt - metabolism; Recombinant Proteins - pharmacology; Signal Transduction; Synergistic effect; Traumatic brain injury; Tumor necrosis factor-TNF; Umbilical cord
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms222111995

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 ( < 0.05). Inflammatory cytokines were downregulated by the treatments and attenuated most by the combination therapy ( < 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 ( < 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.