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Intranasal Erythropoietin Protects CA1 Hippocampal Cells, Modulated by Specific Time Pattern Molecular Changes After Ischemic Damage in Rats

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Abstract

Erythropoietin, a multitarget molecule exhibited neuroprotective properties, especially against cerebral ischemia. However, little effort has been made to determinate both the administration pathway and doses that diminishes neuronal damage. In this study, we investigate the effect on CA1 region of different intranasal doses of rHuEPO (500, 1000 and 2500 IU/kg) applied in distinct post-damage times (1, 6, and 24 h) against ischemic cellular damage. Furthermore, most effective dose and time were used to evaluate gen and protein expression changes in 3 key molecules (EPO, EPOR, and βcR). We established that CA1-region present histopathological damage in this ischemia model and that rHuEPO protects cells against damage, particularly at 1000 IU dose. Molecular data shows that EPO and EPOR gene expression are upregulated in a short term after damage treatment with rHuEPO (1 h); oppositely, BcR is upregulated in ischemic and Isc + EPO. Protein expression data displays no changes on EPO expression in evaluated times after treatment, but a tendency to increase 24 h after damage; in the opposite way, EPOR is upregulated significantly 6 h after treatment and this effect last until 24 h. So, our data suggest that a single intranasal dose of rHuEPO (1 h post-injury) provides histological neurorestoration in CA1 hippocampal region, even if we did not observe a dose-dependent dose effect, the medium dose evaluated (1000 UI/kg of b.w.) was more effective and sufficient for induces molecular changes that provides a platform for neuroprotection.

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Funding

This work was supported by the Universidad de Guadalajara Program (P3E2018, Pro/SNI 2018, Strengthening Research 2018).

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  1. Laboratorio de Neurobiología Celular, Departamento de Biología Celular y Molecular, Universidad de Guadalajara, Guadalajara, Jalisco, Mexico

    R. J. Macias-Velez, L. Fukushima-Díaz de León & M. C. Rivera-Cervantes

  2. Laboratorio de Regeneración Neural y Desarrollo Neural, Departamento de Biología Celular y Molecular, Universidad de Guadalajara, Guadalajara, Jalisco, Mexico

    C. Beas-Zárate

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  1. R. J. Macias-Velez
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All procedures performed in studies involving animals were in accordance with the ethical national regulations (NOM-062-ZOO-1999) and standards of Guadalajara University’s Bioethics Committee at which the studies were conducted (CC/NN 11-12/00/2012).

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Macias-Velez, R.J., Fukushima-Díaz de León, L., Beas-Zárate, C. et al. Intranasal Erythropoietin Protects CA1 Hippocampal Cells, Modulated by Specific Time Pattern Molecular Changes After Ischemic Damage in Rats. J Mol Neurosci 68, 590–602 (2019). https://doi.org/10.1007/s12031-019-01308-w

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