Methylated urolithin A, mitigates cognitive impairment by inhibiting NLRP3 inflammasome and ameliorating mitochondrial dysfunction in aging mice

Effective therapeutic interventions for elderly patients are lacking, despite advances in pharmacotherapy. Methylated urolithin A (mUro A), a modified ellagitannin (ET)-derived metabolite, exhibits anti-inflammatory, antioxidative, and anti-apoptotic effects. Current research has primarily investiga...

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Veröffentlicht in:Neuropharmacology 2024-07, Vol.252, p.109950-109950, Article 109950
Hauptverfasser: Chen, Peng, Wang, Yulai, Xie, Jing, Lei, Jiexin, Zhou, Benhong
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Wang, Yulai
Xie, Jing
Lei, Jiexin
Zhou, Benhong
description Effective therapeutic interventions for elderly patients are lacking, despite advances in pharmacotherapy. Methylated urolithin A (mUro A), a modified ellagitannin (ET)-derived metabolite, exhibits anti-inflammatory, antioxidative, and anti-apoptotic effects. Current research has primarily investigated the neuroprotective effects of mUroA in aging mice and explored the underlying mechanisms. Our study used an in vivo aging model induced by d-galactose (D-gal) to show that mUro A notably improved learning and memory, prevented synaptic impairments by enhancing synaptic protein expression and increasing EPSCs, and reduced oxidative damage in aging mice. mUro A alleviated the activation of the NOD-like receptor thermal protein domain-associated protein 3 (NLRP3) inflammasome, leading to reduced glial cell activity and neuroinflammation in both accelerated aging and naturally senescent mouse models. Moreover, mUroA enhanced the activity of TCA cycle enzymes (PDH, CS, and OGDH), decreased 8-OHdG levels, and raised ATP and NAD+ levels within the mitochondria. At the molecular level, mUro A decreased phosphorylated p53 levels and increased the expression of peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α), thus enhancing mitochondrial function. In conclusion, mUro A alleviates cognitive impairment in aging mice by suppressing neuroinflammation through NLRP3 inflammasome inhibition and restoring mitochondrial function via the p53-PGC-1α pathway. This suggests its potential therapeutic agent for brain aging and aging-related diseases. •HPLC analysis revealed that methylated urolithin A accumulated in the brain tissue of both normal mice and D-gal-induced aging mice, indicating its ability to readily penetrate the blood-brain barrier.•Methylated urolithin A improved learning and memory, prevented synaptic impairments by enhancing synaptic protein expression and increasing sEPSCs, and reduced oxidative damage in aging mice.•Methylated urolithin A alleviated cognitive impairment in aging mice by suppressing neuroinflammation through NLRP3 inflammasome inhibition and restoring mitochondrial function via the p53-PGC-1α pathway.
doi_str_mv 10.1016/j.neuropharm.2024.109950
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Methylated urolithin A (mUro A), a modified ellagitannin (ET)-derived metabolite, exhibits anti-inflammatory, antioxidative, and anti-apoptotic effects. Current research has primarily investigated the neuroprotective effects of mUroA in aging mice and explored the underlying mechanisms. Our study used an in vivo aging model induced by d-galactose (D-gal) to show that mUro A notably improved learning and memory, prevented synaptic impairments by enhancing synaptic protein expression and increasing EPSCs, and reduced oxidative damage in aging mice. mUro A alleviated the activation of the NOD-like receptor thermal protein domain-associated protein 3 (NLRP3) inflammasome, leading to reduced glial cell activity and neuroinflammation in both accelerated aging and naturally senescent mouse models. Moreover, mUroA enhanced the activity of TCA cycle enzymes (PDH, CS, and OGDH), decreased 8-OHdG levels, and raised ATP and NAD+ levels within the mitochondria. At the molecular level, mUro A decreased phosphorylated p53 levels and increased the expression of peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α), thus enhancing mitochondrial function. In conclusion, mUro A alleviates cognitive impairment in aging mice by suppressing neuroinflammation through NLRP3 inflammasome inhibition and restoring mitochondrial function via the p53-PGC-1α pathway. This suggests its potential therapeutic agent for brain aging and aging-related diseases. •HPLC analysis revealed that methylated urolithin A accumulated in the brain tissue of both normal mice and D-gal-induced aging mice, indicating its ability to readily penetrate the blood-brain barrier.•Methylated urolithin A improved learning and memory, prevented synaptic impairments by enhancing synaptic protein expression and increasing sEPSCs, and reduced oxidative damage in aging mice.•Methylated urolithin A alleviated cognitive impairment in aging mice by suppressing neuroinflammation through NLRP3 inflammasome inhibition and restoring mitochondrial function via the p53-PGC-1α pathway.</description><identifier>ISSN: 0028-3908</identifier><identifier>EISSN: 1873-7064</identifier><identifier>DOI: 10.1016/j.neuropharm.2024.109950</identifier><identifier>PMID: 38636727</identifier><language>eng</language><publisher>England: Elsevier Ltd</publisher><subject>Aging ; Aging - drug effects ; Aging - metabolism ; Animals ; Cognitive Dysfunction - drug therapy ; Cognitive Dysfunction - metabolism ; Cognitive function ; Coumarins - pharmacology ; Galactose ; Inflammasomes - drug effects ; Inflammasomes - metabolism ; Male ; Mice ; Mice, Inbred C57BL ; Mitochondria - drug effects ; Mitochondria - metabolism ; Mitochondrial function ; mUro A ; Neuroinflammation ; Neuroprotective Agents - pharmacology ; NLR Family, Pyrin Domain-Containing 3 Protein - metabolism ; NLRP3 ; Oxidative Stress - drug effects ; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha - metabolism</subject><ispartof>Neuropharmacology, 2024-07, Vol.252, p.109950-109950, Article 109950</ispartof><rights>2024 Elsevier Ltd</rights><rights>Copyright © 2024 Elsevier Ltd. 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Methylated urolithin A (mUro A), a modified ellagitannin (ET)-derived metabolite, exhibits anti-inflammatory, antioxidative, and anti-apoptotic effects. Current research has primarily investigated the neuroprotective effects of mUroA in aging mice and explored the underlying mechanisms. Our study used an in vivo aging model induced by d-galactose (D-gal) to show that mUro A notably improved learning and memory, prevented synaptic impairments by enhancing synaptic protein expression and increasing EPSCs, and reduced oxidative damage in aging mice. mUro A alleviated the activation of the NOD-like receptor thermal protein domain-associated protein 3 (NLRP3) inflammasome, leading to reduced glial cell activity and neuroinflammation in both accelerated aging and naturally senescent mouse models. Moreover, mUroA enhanced the activity of TCA cycle enzymes (PDH, CS, and OGDH), decreased 8-OHdG levels, and raised ATP and NAD+ levels within the mitochondria. At the molecular level, mUro A decreased phosphorylated p53 levels and increased the expression of peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α), thus enhancing mitochondrial function. In conclusion, mUro A alleviates cognitive impairment in aging mice by suppressing neuroinflammation through NLRP3 inflammasome inhibition and restoring mitochondrial function via the p53-PGC-1α pathway. 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Wang, Yulai ; Xie, Jing ; Lei, Jiexin ; Zhou, Benhong</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c319t-5500c1cc4cc859eaa4a759eb593bf93bbabb243db0b6cd66cbede5ddbac9824c3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2024</creationdate><topic>Aging</topic><topic>Aging - drug effects</topic><topic>Aging - metabolism</topic><topic>Animals</topic><topic>Cognitive Dysfunction - drug therapy</topic><topic>Cognitive Dysfunction - metabolism</topic><topic>Cognitive function</topic><topic>Coumarins - pharmacology</topic><topic>Galactose</topic><topic>Inflammasomes - drug effects</topic><topic>Inflammasomes - metabolism</topic><topic>Male</topic><topic>Mice</topic><topic>Mice, Inbred C57BL</topic><topic>Mitochondria - drug effects</topic><topic>Mitochondria - metabolism</topic><topic>Mitochondrial function</topic><topic>mUro A</topic><topic>Neuroinflammation</topic><topic>Neuroprotective Agents - pharmacology</topic><topic>NLR Family, Pyrin Domain-Containing 3 Protein - metabolism</topic><topic>NLRP3</topic><topic>Oxidative Stress - drug effects</topic><topic>Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha - metabolism</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Chen, Peng</creatorcontrib><creatorcontrib>Wang, Yulai</creatorcontrib><creatorcontrib>Xie, Jing</creatorcontrib><creatorcontrib>Lei, Jiexin</creatorcontrib><creatorcontrib>Zhou, Benhong</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><jtitle>Neuropharmacology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Chen, Peng</au><au>Wang, Yulai</au><au>Xie, Jing</au><au>Lei, Jiexin</au><au>Zhou, Benhong</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Methylated urolithin A, mitigates cognitive impairment by inhibiting NLRP3 inflammasome and ameliorating mitochondrial dysfunction in aging mice</atitle><jtitle>Neuropharmacology</jtitle><addtitle>Neuropharmacology</addtitle><date>2024-07-01</date><risdate>2024</risdate><volume>252</volume><spage>109950</spage><epage>109950</epage><pages>109950-109950</pages><artnum>109950</artnum><issn>0028-3908</issn><eissn>1873-7064</eissn><abstract>Effective therapeutic interventions for elderly patients are lacking, despite advances in pharmacotherapy. Methylated urolithin A (mUro A), a modified ellagitannin (ET)-derived metabolite, exhibits anti-inflammatory, antioxidative, and anti-apoptotic effects. Current research has primarily investigated the neuroprotective effects of mUroA in aging mice and explored the underlying mechanisms. Our study used an in vivo aging model induced by d-galactose (D-gal) to show that mUro A notably improved learning and memory, prevented synaptic impairments by enhancing synaptic protein expression and increasing EPSCs, and reduced oxidative damage in aging mice. mUro A alleviated the activation of the NOD-like receptor thermal protein domain-associated protein 3 (NLRP3) inflammasome, leading to reduced glial cell activity and neuroinflammation in both accelerated aging and naturally senescent mouse models. Moreover, mUroA enhanced the activity of TCA cycle enzymes (PDH, CS, and OGDH), decreased 8-OHdG levels, and raised ATP and NAD+ levels within the mitochondria. At the molecular level, mUro A decreased phosphorylated p53 levels and increased the expression of peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α), thus enhancing mitochondrial function. In conclusion, mUro A alleviates cognitive impairment in aging mice by suppressing neuroinflammation through NLRP3 inflammasome inhibition and restoring mitochondrial function via the p53-PGC-1α pathway. This suggests its potential therapeutic agent for brain aging and aging-related diseases. •HPLC analysis revealed that methylated urolithin A accumulated in the brain tissue of both normal mice and D-gal-induced aging mice, indicating its ability to readily penetrate the blood-brain barrier.•Methylated urolithin A improved learning and memory, prevented synaptic impairments by enhancing synaptic protein expression and increasing sEPSCs, and reduced oxidative damage in aging mice.•Methylated urolithin A alleviated cognitive impairment in aging mice by suppressing neuroinflammation through NLRP3 inflammasome inhibition and restoring mitochondrial function via the p53-PGC-1α pathway.</abstract><cop>England</cop><pub>Elsevier Ltd</pub><pmid>38636727</pmid><doi>10.1016/j.neuropharm.2024.109950</doi><tpages>1</tpages><orcidid>https://orcid.org/0000-0003-4936-2064</orcidid></addata></record>
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source MEDLINE; Access via ScienceDirect (Elsevier)
subjects Aging
Aging - drug effects
Aging - metabolism
Animals
Cognitive Dysfunction - drug therapy
Cognitive Dysfunction - metabolism
Cognitive function
Coumarins - pharmacology
Galactose
Inflammasomes - drug effects
Inflammasomes - metabolism
Male
Mice
Mice, Inbred C57BL
Mitochondria - drug effects
Mitochondria - metabolism
Mitochondrial function
mUro A
Neuroinflammation
Neuroprotective Agents - pharmacology
NLR Family, Pyrin Domain-Containing 3 Protein - metabolism
NLRP3
Oxidative Stress - drug effects
Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha - metabolism
title Methylated urolithin A, mitigates cognitive impairment by inhibiting NLRP3 inflammasome and ameliorating mitochondrial dysfunction in aging mice
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