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.
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Acknowledgements
This study was supported in part by grants from Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq-Brazil), Fundo de Incentivo à Pesquisa e Eventos/Hospital de Clínicas de Porto Alegre (FIPE/HCPA-Brazil) and Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES-Brazil).
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All authors contributed in this work. RBF, LSF, CAN and MFMR planned the study design. RBF, NLM, YMC, SKS and FN conducted the experiments. RBF and LSF performed data analysis and wrote the manuscript. RBF, LSF and IDT prepared the figures. RBF, LSF, NLM and IDT revised critically the manuscript. LSF, CAN and MFMR were recipient of funding used to support the study.
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All applicable international, national, and/or institutional guidelines for the care and use of animals were followed. This study was approved by the Institutional Animal Care and Use Committees of Federal University of Rio Grande do Sul (UFRGS, #26669) and Hospital de Clínicas de Porto Alegre (HCPA, #14–0578).
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Fabres, R.B., Montes, N.L., Camboim, Y.d. et al. Long-Lasting Actions of Progesterone Protect the Neonatal Brain Following Hypoxia-Ischemia. Cell Mol Neurobiol 40, 1417–1428 (2020). https://doi.org/10.1007/s10571-020-00827-0
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DOI: https://doi.org/10.1007/s10571-020-00827-0