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Mol Nutr Food Res. 2019 May;63(10):e1801237. doi: 10.1002/mnfr.201801237. Epub 2019 Mar 7.

Induction of Autophagy and Activation of SIRT-1 Deacetylation Mechanisms Mediate Neuroprotection by the Pomegranate Metabolite Urolithin A in BV2 Microglia and Differentiated 3D Human Neural Progenitor Cells.

Author information

1
Department of Pharmacy, School of Applied Sciences, University of Huddersfield, Huddersfield, HD1 3DH, United Kingdom.
2
Neurochemistry and Neuroimmunology Research Group, Department of Psychiatry and Psychotherapy, Medical Center-University of Freiburg, Hauptstrasse 5, 79104, Freiburg, Germany.

Abstract

SCOPE:

Urolithin A is an anti-inflammatory and neuroprotective gut-derived metabolite from ellagitannins and ellagic acid in pomegranate, berries, and nuts. The roles of SIRT-1 and autophagy in the neuroprotective activity of urolithin A are investigated.

METHODS AND RESULTS:

Analyses of culture supernatants from lipopolysaccharide-stimulated BV2 microglia show that urolithin A (2.5-10 µm) produced significant reduction in the production of nitrite, tumor necrosis factor (TNF)-α and IL-6. The anti-inflammatory effect of the compound is reversed in the presence of sirtuin (SIRT)-1 and the autophagy inhibitors EX527 and chloroquine, respectively. Protein analyses reveal reduction in p65 and acetyl-p65 protein. Treatment of BV2 microglia with urolithin A results in increased SIRT-1 activity and nuclear protein, while induction of autophagy by the compound is demonstrated using autophagy fluorescent and autophagy LC3 HiBiT reporter assays. Viability assays reveal that urolithin A produces a neuroprotective effect in APPSwe-transfected ReNcell VM human neural cells, which is reversed in the presence of EX527 and chloroquine. Increase in both SIRT-1 and autophagic activities are also detected in these cells following treatment with urolithin A.

CONCLUSIONS:

It has been proposed that SIRT-1 activation and induction of autophagy are involved in the neuroprotective activity of urolithin A in brain cells.

KEYWORDS:

3D human neural progenitor cells; SIRT-1; autophagy; microglia; neuroinflammation; neuroprotective; urolithin A

PMID:
30811877
DOI:
10.1002/mnfr.201801237

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