Long-Lasting Actions of Progesterone Protect the Neonatal Brain Following Hypoxia-Ischemia
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ORIGINAL RESEARCH
Long‑Lasting Actions of Progesterone Protect the Neonatal Brain Following Hypoxia‑Ischemia Rafael Bandeira Fabres1,2 · Nathalia Lima Montes1 · Yahi de Menezes Camboim1 · Samir Khal de Souza1,2 · Fabrício Nicola3,4 · Isadora D’Ávila Tassinari1,2 · Maria Flavia Marques Ribeiro1,2 · Carlos Alexandre Netto2,3,4 · Luciano Stürmer de Fraga1,2 Received: 14 October 2019 / Accepted: 2 March 2020 © Springer Science+Business Media, LLC, part of Springer Nature 2020
Abstract Neonatal hypoxia–ischemia (HI) is the leading cause of mortality and morbidity in newborns, occurring in approximately 2% of live births. Neuroprotective actions of progesterone (PROG) have already been described in animal models of brain lesions. However, PROG actions on neonates are still controversial. Here, we treated male Wistar rats exposed to HI with PROG. Five experimental groups were defined (n = 6/group) according to the scheme of PROG administration (10 mg/kg): SHAM (animals submitted to a fictitious surgery, without ischemia induction, and maintained under normoxia), HI (animals undergoing HI), BEFORE (animals undergoing HI and receiving PROG immediately before HI), AFTER (animals undergoing HI and receiving PROG at 6 and 24 h after HI) and BEFORE/AFTER (animals undergoing HI and receiving PROG immediately before and 6 and 24 h after HI). At P14 (7 days following HI), the volumes of lesion of the cerebral hemisphere and the hippocampus ipsilateral to the cerebral ischemia were evaluated, along with p-Akt, cleaved caspase-3 and GFAP expression in the hippocampus. PROG reduces the loss of brain tissue caused by HI. Moreover, when administered after HI, PROG was able to increase p-Akt expression and reduce both cleaved caspase-3 and GFAP expression in the hippocampus. In summary, it was possible to observe a neuroprotective action of PROG on the brain of neonatal animals exposed to experimental HI. This is the first study suggesting PROG-dependent Akt activation is able to regulate negatively cleaved caspase-3 and GFAP expression protecting neonatal hypoxic-ischemic brain tissue from apoptosis and reactive gliosis. Keywords Neonatal hypoxia–ischemia · Akt · GFAP · Caspase-3 · Astrogliosis · Neuroprotection
Introduction
* Luciano Stürmer de Fraga [email protected] 1
Departamento de Fisiologia, Federal University of Rio Grande do Sul (UFRGS), Sarmento Leite, 500, Porto Alegre 90050‑170, Brazil
2
Programa de Pós‑Graduação em Ciências Biológicas: Fisiologia, Federal University of Rio Grande do Sul (UFRGS), Sarmento Leite, 500, Porto Alegre 90050‑170, Brazil
3
Departamento de Bioquímica, Federal University of Rio Grande do Sul (UFRGS), Ramiro Barcelos, 2600, Porto Alegre 90035‑003, Brazil
4
Programa de Pós‑Graduação em Ciências Biológicas: Neurociências, Federal University of Rio Grande do Sul (UFRGS), Sarmento Leite, 500, Porto Alegre 90050‑170, Brazil
Neonatal hypoxia–ischemia (HI) is a condition associated with a variety of harmful events, such as perinatal asphyxia, intraventricular hemorrhage, stroke amon
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