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

Nicholas A. DaSilva; Pragati P. Nahar; Hang Ma; Aseel Eid; Zhengxi Wei; Susan Meschwitz; Nasser H. Zawia; Angela L. Slitt; Navindra P. Seeram

doi:10.1080/1028415X.2017.1360558

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

Nicholas A. DaSilva
, Pragati P. Nahar
, Hang Ma
, Aseel Eid
, Zhengxi Wei
, Susan Meschwitz
, Nasser H. Zawia^*
, Angela L. Slitt
, Navindra P. Seeram

^*Corresponding author for this work

University of Rhode Island
Salve Regina University

Research output: Contribution to journal › Article › peer-review

85 Citations (Scopus)

Abstract

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.

Original language	English
Pages (from-to)	185-195
Number of pages	11
Journal	Nutritional Neuroscience
Volume	22
Issue number	3
DOIs	https://doi.org/10.1080/1028415X.2017.1360558
Publication status	Published - 4 Mar 2019
Externally published	Yes

Keywords

Gut microflora
Neuroinflammation
Neuroprotective
Pomegranate
Urolithins

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10.1080/1028415X.2017.1360558

Cite this

@article{1af2b50496a34cb99baeb5e789dbcdff,

title = "Pomegranate ellagitannin-gut microbial-derived metabolites, urolithins, inhibit neuroinflammation in vitro",

abstract = " Objectives: Urolithins, ellagitannin-gut microbial-derived metabolites, have been reported to mediate pomegranate{\textquoteright}s neuroprotective effects against Alzheimer{\textquoteright}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{\textquoteright}s neuroprotective effects against AD.",

keywords = "Gut microflora, Neuroinflammation, Neuroprotective, Pomegranate, Urolithins",

author = "DaSilva, \{Nicholas A.\} and Nahar, \{Pragati P.\} and Hang Ma and Aseel Eid and Zhengxi Wei and Susan Meschwitz and Zawia, \{Nasser H.\} and Slitt, \{Angela L.\} and Seeram, \{Navindra P.\}",

note = "Publisher Copyright: {\textcopyright} 2017, {\textcopyright} 2017 Informa UK Limited, trading as Taylor \& Francis Group.",

year = "2019",

month = mar,

day = "4",

doi = "10.1080/1028415X.2017.1360558",

language = "English",

volume = "22",

pages = "185--195",

journal = "Nutritional Neuroscience",

issn = "1028-415X",

publisher = "Taylor and Francis Ltd.",

number = "3",

}

TY - JOUR

T1 - Pomegranate ellagitannin-gut microbial-derived metabolites, urolithins, inhibit neuroinflammation in vitro

AU - DaSilva, Nicholas A.

AU - Nahar, Pragati P.

AU - Ma, Hang

AU - Eid, Aseel

AU - Wei, Zhengxi

AU - Meschwitz, Susan

AU - Zawia, Nasser H.

AU - Slitt, Angela L.

AU - Seeram, Navindra P.

PY - 2019/3/4

Y1 - 2019/3/4

N2 - 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.

AB - 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.

KW - Gut microflora

KW - Neuroinflammation

KW - Neuroprotective

KW - Pomegranate

KW - Urolithins

UR - https://www.scopus.com/pages/publications/85027020877

U2 - 10.1080/1028415X.2017.1360558

DO - 10.1080/1028415X.2017.1360558

M3 - Article

C2 - 28784051

AN - SCOPUS:85027020877

SN - 1028-415X

VL - 22

SP - 185

EP - 195

JO - Nutritional Neuroscience

JF - Nutritional Neuroscience

IS - 3

ER -

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

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Keywords

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