Abstract
Therapeutic hypothermia (TH) is the standard treatment for neonatal hypoxia-ischemia (HI) with a time window limited up to 6 h post injury. However, influence of sexual dimorphism in the therapeutic window for TH has not yet been elucidated in animal models of HI. Therefore, the aim of this study was to investigate the most effective time window to start TH in male and female rats submitted to neonatal HI. Wistar rats (P7) were divided into the following groups: NAÏVE and SHAM (control groups), HI (submitted to HI) and TH (submitted to HI and TH; 32ºC for 5 h). TH was started at 2 h (TH-2 h group), 4 h (TH-4 h group), or 6 h (TH-6 h group) after HI. At P14, animals were subjected to behavioural tests, volume of lesion and reactive astrogliosis assessments. Male and female rats from the TH-2 h group showed reduction in the latency of behavioral tests, and decrease in volume of lesion and intensity of GFAP immunofluorescence. TH-2 h females also showed reduction of degenerative cells and morphological changes in astrocytes. Interestingly, females from the TH-6 h group showed an increase in volume of lesion and in number of degenerative hippocampal cells, associated with worse behavioral performance. Together, these results indicate that TH neuroprotection is time- and sex-dependent. Moreover, TH started later (6 h) can worsen volume of brain lesion in females. These data indicate the need to develop specific therapeutic protocols for each sex and reinforce the importance of early onset of the hypothermic treatment.
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“The datasets generated during and/or analysed during the current study are available from the corresponding author on reasonable request”.
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This study was supported in part by grants from Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq), Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) and, Financiadora de Estudos e Projetos (FINEP). We would also like to thank the Laboratório de Análises de Amostras Biológicas por Fluorescência (LabFluor - UFRGS) for the support in all analysis.
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All authors contributed in this work. RBF, LSF, CAN and planned the study design. RBF, RRN, MMM, MKGA, APRM, IDT and ESF conducted the experiments. RBF performed data analysis and wrote the manuscript. RBF and IDT prepared the figures. RBF, EFS, LFS and CAN revised critically the manuscript. LSF and CAN were recipient of funding used to support the study.
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All procedures involving animals were in accordance with the precepts of the National and International Guidelines, especially Law 11,794 of November 8, 2008, Decree 6899 of July 15, 2009, and as edited by the National Council for the Control of Animal Experimentation (CONCEA), was approved by the Institutional Animal Care and Use Committee of Federal University of Rio Grande do Sul (UFRGS, #31442).
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Fabres, R.B., Nunes, R.R., de Medeiros de Mattos, M. et al. Therapeutic hypothermia for the treatment of neonatal hypoxia-ischemia: sex-dependent modulation of reactive astrogliosis. Metab Brain Dis 37, 2315–2329 (2022). https://doi.org/10.1007/s11011-022-01030-4
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DOI: https://doi.org/10.1007/s11011-022-01030-4