Pomegranate ellagitannin-gut microbial-derived metabolites, urolithins, inhibit neuroinflammation in vitro.

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 H2O2-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 E2, 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 H2O2-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.

Pomegranate extract modulates processing of amyloid-ß precursor protein in an aged Alzheimer's disease animal model.

Accumulating research supports the neuroprotective effects of pomegranate (Punica granatum) juice and extracts against Alzheimer's disease (AD) but there is limited data available in animal models. Here we investigated the effects of a standardized pomegranate extract (PE) on AD pathology in an aged transgenic AD animal model (R1.40).The mice (age 24-30 months) received either PE (at 100 and 200 mg/kg) or a control solution daily for three weeks, and were evaluated in the Morris water maze and the Y-maze for improvements in spatial long-term and working memory functions. Cortical amyloid-ß precursor protein (APP) and amyloid-ß (Aß) levels, along with other relevant biomarkers for AD, were measured in brain tissues. PE did not improve cognitive performance of the mice, but altered levels and ratio of the Aß42 and Aß40 peptides which would favor a diminution in AD pathogenesis. Further analysis revealed that this reversal could be the product of the modification of γ-secretase enzyme activity, the enzyme involved in the generation of these Aß isoforms. Our findings support a specific anti-amyloidogenic mechanism of a pomegranate extract in this aged AD animal model.