Pomegranate ellagitannin-gut microbial-derived metabolites, urolithins, inhibit neuroinflammation in vitro
Date of Original Version
Objectives: Urolithins, ellagitannin-gut microbial-derived metabolites, have been reported to mediate pomegranate’s neuroprotective effects against Alzheimer’s disease (AD), but there are limited data on their effects against neuroinflammation. Herein, we: (1) evaluated whether urolithins (urolithins A and B and their methylated derivatives) attenuate neuroinflammation in murine BV-2 microglia and human SH-SY5Y neurons, and (2) evaluated hippocampus of transgenic AD (R1.40) mice administered a pomegranate extract (PE; 100 or 200 mg/kg/day for 3 weeks) for inflammatory biomarkers. Methods: Effects of urolithins (10 μM) on inflammatory biomarkers were evaluated in lipopolysaccharide (LPS)-stimulated BV-2 microglia. In a non-contact co-culture cell model, SH-SY5Y cell viability was assessed after exposure to media collected from LPS-BV-2 cells treated with or without urolithins. Effects of urolithins on apoptosis and caspase 3/7 and 9 release from H 2 O 2 -induced oxidative stress of BV-2 and SH-SY5Y cells were assessed. Hippocampal tissues of vehicle and PE-treated transgenic R1.40 mice were evaluated for gene expression of inflammatory biomarkers by qRT-PCR. Results: Urolithins decreased media levels of nitric oxide, interleukin 6 (IL-6), prostaglandin E 2 , and tumor necrosis factor alpha from LPS-BV-2 microglia. In the co-culture cell model, media from LPS-BV-2 cells treated with urolithins preserved SH-SY5Y cell viability greater than media from cells treated without urolithins. Urolithins mitigated apoptosis and caspase 3/7 and 9 release from H 2 O 2 -induced oxidative stress of BV-2 and SH-SY5Y cells. While not statistically significant, inflammatory biomarkers (TNF-α, COX-2, IL-1, and IL-6) appeared to follow a decreasing trend in the hippocampus of high-dose PE-treated animals compared to controls. Discussion: The attenuation of neuroinflammation by urolithins may contribute, in part, toward pomegranate’s neuroprotective effects against AD.
DaSilva, Nicholas A., Pragati P. Nahar, Hang Ma, Aseel Eid, Zhengxi Wei, Susan Meschwitz, Nasser H. Zawia, Angela L. Slitt, and Navindra P. Seeram. "Pomegranate ellagitannin-gut microbial-derived metabolites, urolithins, inhibit neuroinflammation in vitro." Nutritional Neuroscience 22, 3 (2019): 185-195. doi:10.1080/1028415X.2017.1360558.