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11β-HSD1 Inhibition by RL-118 Promotes Autophagy and Correlates with Reduced Oxidative Stress and Inflammation, Enhancing Cognitive Performance in SAMP8 Mouse Model

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Abstract

Elevated glucocorticoid (GC) exposure is widely accepted as a key factor in the age-related cognitive decline in rodents and humans. 11β-HSD1 is a key enzyme in the GCs pathway, catalyzing the conversion of 11β-dehydrocorticosterone to corticosterone in mice, with possible implications in neurodegenerative processes and cognitive impairment. Here, we determined the effect of a new 11β-HSD1 inhibitor, RL-118, administered to 12-month-old senescence-accelerated mouse-prone 8 (SAMP8) mice with neuropathological AD-like hallmarks and widely used as a rodent model of cognitive dysfunction. Behavioral tests (open field and object location) and neurodegeneration molecular markers were studied. After RL-118 treatment, increased locomotor activity and cognitive performance were found. Likewise, we found changes in hippocampal autophagy markers such as Beclin1, LC3B, AMPKα, and mTOR, indicating a progression in the autophagy process. In line with autophagy increase, a diminution in phosphorylated tau species (Ser 396 and Ser 404) jointly with an increase in ADAM10 and sAPPα indicated that an improvement in removing the abnormal proteins by autophagy might be implicated in the neuroprotective role of the 11β-HSD1 inhibitor. In addition, gene expression of oxidative stress (OS) and inflammatory markers, such as Hmox1, Aldh2, Il-1β, and Ccl3, were reduced in old treated mice in comparison to that of the control group. Consistent with this, we further demonstrate a significant correlation with autophagy markers and cognitive improvement and significant inverse correlation with autophagy, OS, and neuroinflammation markers. We concluded that inhibition of 11β-HSD1 by RL-118 prevented neurodegenerative processes and cognitive decline, acting on autophagy process, being an additional neuroprotective mechanism not described previously.

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Acknowledgments

We thank Maggie Brunner, M.A., for revising the language and style of the manuscript.

Funding

This study was supported by the Ministerio de Economía y Competitividad of Spain SAF2016-33307 and SAF2014-57094R. D.P-I. and R.L. thank the Spanish Ministerio de Educación Cultura y Deporte for a PhD Grant (FPU program). Authors belong to 2017SGR106 from AGAUR, Catalonia.

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Authors and Affiliations

  1. Secció de Farmacologia i Toxicologia and Institut de Neurociències, Facultat de Farmàcia i Ciències de l’Alimentació, Universitat de Barcelona, Av. Joan XXIII, 27-31, 08028, Barcelona, Spain

    Dolors Puigoriol-Illamola, Christian Griñán-Ferré, Foteini Vasilopoulou & Mercè Pallàs

  2. Laboratori de Química Farmacèutica (Unitat Associada al CSIC), and Institute of Biomedicine (IBUB), Facultat de Farmàcia i Ciències de l’Alimentació, Universitat de Barcelona, Av. Joan XXIII, 27-31, 08028, Barcelona, Spain

    Rosana Leiva & Santiago Vázquez

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  1. Dolors Puigoriol-Illamola
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Contributions

Participated in research design: Puigoriol-Illamola, Griñan-Ferré., Pallàs.

Conducted experiments: Puigoriol-Illamola, Griñan-Ferré, Vasilopoulou, Leiva.

Contributed new reagents or analytic tools: Leiva, Vazquez.

Performed data analysis: Puigoriol-Illamola, Griñan-Ferré.

Wrote or contributed to the writing of the manuscript: Puigoriol-Illamola, Griñán-Ferré, Leiva, Vazquez, Pallàs

Corresponding author

Correspondence to Mercè Pallàs.

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Puigoriol-Illamola, D., Griñán-Ferré, C., Vasilopoulou, F. et al. 11β-HSD1 Inhibition by RL-118 Promotes Autophagy and Correlates with Reduced Oxidative Stress and Inflammation, Enhancing Cognitive Performance in SAMP8 Mouse Model. Mol Neurobiol 55, 8904–8915 (2018). https://doi.org/10.1007/s12035-018-1026-8

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  • DOI: https://doi.org/10.1007/s12035-018-1026-8

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