{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,4]],"date-time":"2026-11-04T21:17:34Z","timestamp":1793827054580,"version":"4.6.1"},"reference-count":52,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2023,2,23]],"date-time":"2023-02-23T00:00:00Z","timestamp":1677110400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Pharmacol."],"abstract":"<jats:p>The pathophysiology of depression is heavily dependent on inflammation. Evidence suggests that the etiology of depression is linked with NLRP3 inflammasome-induced inflammation. Therefore, blocking the activated NLRP3 inflammasome may be beneficial for treating depression. Due to the limitations of currently available antidepressants, it is necessary to develop novel, safe, and affordable drugs for the treatment of depression. A natural coumarin derivative named 4-methylesculetin (4-MESC) possesses anti-inflammatory properties. However, the role of 4-MESC as an antidepressant has not been elucidated. Therefore, in this study, we explored the antidepressant-like effects of 4-MESC and its underlying molecular mechanism through the modulation of the NLRP3 inflammasome. The docking and molecular dynamic simulation studies revealed that 4-MESC has a higher affinity for the NLRP3 PYD. Blood\u2013brain barrier permeability was confirmed using the SwissADME pharmacokinetic tool. High doses (50\u00a0mg\/kg) of 4-MESC significantly reduced the immobility duration in the tail-suspension test (TST) and forced swim test (FST) without changing the overall locomotor activity in the female Swiss albino mice that were subjected to lipopolysaccharide (LPS). LPS-induced pro-inflammatory cytokines such as IL-6 and TNF-\u03b1 were reduced in serum and brain tissues using 4-MESC. 4-MESC\u2019s neuroprotective effects are mediated by increased brain-derived neurotrophic factor (BDNF) and decreased cortisol levels. 4-MESC markedly reduced LPS-induced elevated levels of ROS and lipid peroxidation (malondialdehyde levels) and enhanced the superoxide dismutase (SOD) activity and glutathione levels, which revealed its anti-oxidant potential against oxidative stress. 4-MESC diminished the expression levels of NF-\u03baBp65, IL-6, NLRP3, caspase-1, gasdermin D, and IL-1\u03b2 in the hippocampus. These findings demonstrated that 4-MESC exhibited antidepressant-like effects by inhibiting the NLRP3 inflammasome. However, other antidepressant mechanisms might also be involved which require further studies.<\/jats:p>","DOI":"10.3389\/fphar.2023.1120508","type":"journal-article","created":{"date-parts":[[2023,2,23]],"date-time":"2023-02-23T04:49:49Z","timestamp":1677127789000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":21,"title":["4-Methylesculetin ameliorates LPS-induced depression-like behavior through the inhibition of NLRP3 inflammasome"],"prefix":"10.3389","volume":"14","author":[{"given":"Khushboo","family":"Choudhary","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Surendra Rajit","family":"Prasad","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kiran Bharat","family":"Lokhande","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Krishna","family":"Murti","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sanjiv","family":"Singh","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Velayutham","family":"Ravichandiran","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nitesh","family":"Kumar","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2023,2,23]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"450","DOI":"10.1038\/374450A0","article-title":"A BDNF autocrine loop in adult sensory neurons prevents cell death","volume":"374","author":"Acheson","year":"1995","journal-title":"Nature"},{"key":"B2","doi-asserted-by":"publisher","first-page":"114","DOI":"10.1016\/J.PHRS.2017.04.028","article-title":"Antidepressants induce autophagy dependent-NLRP3-inflammasome inhibition in Major depressive disorder","volume":"121","author":"Alcocer-G\u00f3mez","year":"2017","journal-title":"Pharmacol. Res."},{"key":"B3","doi-asserted-by":"publisher","first-page":"294","DOI":"10.1111\/cns.12230","article-title":"NLRP3 inflammasome: A new target in major depressive disorder","volume":"20","author":"Alcocer-G\u00f3mez","year":"2014","journal-title":"CNS Neurosci. Ther."},{"key":"B4","doi-asserted-by":"publisher","first-page":"111","DOI":"10.1016\/J.BBI.2013.10.017","article-title":"NLRP3 inflammasome is activated in mononuclear blood cells from patients with major depressive disorder","volume":"36","author":"Alcocer-G\u00f3mez","year":"2014","journal-title":"Brain, Behav. Immun."},{"key":"B5","doi-asserted-by":"publisher","first-page":"4874","DOI":"10.1007\/S12035-015-9408-7","article-title":"Stress-induced depressive behaviors require a functional NLRP3 inflammasome","volume":"53","author":"Alcocer-G\u00f3mez","year":"2016","journal-title":"Mol. Neurobiol."},{"key":"B6","doi-asserted-by":"publisher","first-page":"727","DOI":"10.1089\/CAP.2015.0147","article-title":"The relationship between plasma cytokine levels and response to selective serotonin reuptake inhibitor treatment in children and adolescents with depression and\/or anxiety disorders","volume":"26","author":"Amitai","year":"2016","journal-title":"J. Child Adolesc. Psychopharmacol."},{"key":"B7","doi-asserted-by":"publisher","first-page":"4089","DOI":"10.3390\/MOLECULES25184089","article-title":"Anti-inflammatory activity and ROS regulation effect of sinapaldehyde in LPS-stimulated RAW 264.7 macrophages","volume":"25","author":"Baek","year":"2020","journal-title":"Mol. (Basel, Switz."},{"key":"B8","doi-asserted-by":"publisher","first-page":"787","DOI":"10.4049\/JIMMUNOL.0901363","article-title":"Cutting edge: NF-kappaB activating pattern recognition and cytokine receptors license NLRP3 inflammasome activation by regulating NLRP3 expression","volume":"183","author":"Bauernfeind","year":"2009","journal-title":"J. Immunol."},{"key":"B9","doi-asserted-by":"publisher","first-page":"146917","DOI":"10.1016\/j.brainres.2020.146917","article-title":"Repeated psychosocial stress causes glutamic acid decarboxylase isoform-67, oxidative-Nox-2 changes and neuroinflammation in mice: Prevention by treatment with a neuroactive flavonoid, morin","volume":"1744","author":"Ben-Azu","year":"2020","journal-title":"Brain Res."},{"key":"B10","doi-asserted-by":"publisher","first-page":"519","DOI":"10.1126\/science.2821620","article-title":"Release of multiple hormones by a direct action of interleukin-1 on pituitary cells","volume":"238","author":"Bernton","year":"1987","journal-title":"Science"},{"key":"B11","doi-asserted-by":"publisher","first-page":"271359","DOI":"10.1155\/2013\/271359","article-title":"Systemic immune activation leads to neuroinflammation and sickness behavior in mice","volume":"2013","author":"Biesmans","year":"2013","journal-title":"Mediat. Inflamm."},{"key":"B12","doi-asserted-by":"publisher","first-page":"46","DOI":"10.1038\/nrn2297","article-title":"From inflammation to sickness and depression: When the immune system subjugates the brain","volume":"9","author":"Dantzer","year":"2008","journal-title":"Nat. Rev. Neurosci."},{"key":"B13","doi-asserted-by":"publisher","first-page":"327","DOI":"10.1001\/archpsyc.64.3.327","article-title":"The role of dopamine in the pathophysiology of depression","volume":"64","author":"Dunlop","year":"2007","journal-title":"Archives General Psychiatry"},{"key":"B14","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/J.MAM.2008.08.006","article-title":"Glutathione: Overview of its protective roles, measurement, and biosynthesis","volume":"30","author":"Forman","year":"2009","journal-title":"Mol. Aspects Med."},{"key":"B15","doi-asserted-by":"publisher","first-page":"14105","DOI":"10.3390\/ijms140714105","article-title":"Resveratrol inhibits ionising irradiation-induced inflammation in MSCs by activating SIRT1 and limiting NLRP-3 inflammasome activation","volume":"14","author":"Fu","year":"2013","journal-title":"Int. J. Mol. Sci."},{"key":"B16","doi-asserted-by":"publisher","first-page":"134","DOI":"10.1097\/WNR.0000000000000944","article-title":"Evaluation of antidepressant activity of methanolic extract of Saraca asoca bark in a chronic unpredictable mild stress model","volume":"29","author":"Gill","year":"2018","journal-title":"Neuroreport"},{"key":"B17","doi-asserted-by":"publisher","first-page":"381","DOI":"10.1016\/S0006-3223(02)01480-4","article-title":"New insights into the role of cortisol and the glucocorticoid receptor in severe depression","volume":"52","author":"Gold","year":"2002","journal-title":"Biol. Psychiatry"},{"key":"B18","doi-asserted-by":"publisher","first-page":"30","DOI":"10.1016\/j.yfrne.2008.10.001","article-title":"Interleukin-1 (IL-1): A central regulator of stress responses","volume":"30","author":"Goshen","year":"2009","journal-title":"Front. Neuroendocrinol."},{"key":"B19","doi-asserted-by":"publisher","first-page":"1326","DOI":"10.1016\/J.BIOCHI.2013.02.014","article-title":"Antiarthritic and antiinflammatory propensity of 4-methylesculetin, a coumarin derivative","volume":"95","author":"Hemshekhar","year":"2013","journal-title":"Biochimie"},{"key":"B20","doi-asserted-by":"publisher","first-page":"959","DOI":"10.4088\/JCP.V65N0712","article-title":"Incidence and duration of side effects and those rated as bothersome with selective serotonin reuptake inhibitor treatment for depression: Patient report versus physician estimate","volume":"65","author":"Hu","year":"2004","journal-title":"J. Clin. Psychiatry"},{"key":"B21","doi-asserted-by":"publisher","first-page":"105","DOI":"10.1016\/J.BBI.2012.12.008","article-title":"The inflammasome: Pathways linking psychological stress, depression, and systemic illnesses","volume":"31","author":"Iwata","year":"2013","journal-title":"Brain, Behav. Immun."},{"key":"B22","doi-asserted-by":"publisher","first-page":"9","DOI":"10.6116\/kjh.2014.29.5.9","article-title":"Effect of glycyrrhizae radix water extract on the depression induced by LPS in rats","volume":"29","author":"Ko","year":"2014","journal-title":"Korea J. Herbology"},{"key":"B23","doi-asserted-by":"publisher","first-page":"7294","DOI":"10.1080\/07391102.2020.1805019","article-title":"Molecular docking and simulation studies on SARS-CoV-2 Mpro reveals Mitoxantrone, Leucovorin, Birinapant, and Dynasore as potent drugs against COVID-19","volume":"39","author":"Lokhande","year":"2021","journal-title":"J. Biomol. Struct. Dyn."},{"key":"B24","doi-asserted-by":"publisher","first-page":"1189","DOI":"10.1176\/AJP.150.8.1189","article-title":"Interleukin-1 beta: A putative mediator of HPA axis hyperactivity in major depression?","volume":"150","author":"Maes","year":"1993","journal-title":"Am. J. Psychiatry"},{"key":"B25","doi-asserted-by":"publisher","first-page":"2299","DOI":"10.1016\/S0140-6736(18)31948-2","article-title":"Depression","volume":"392","author":"Malhi","year":"2018","journal-title":"Lancet"},{"key":"B26","doi-asserted-by":"publisher","first-page":"7024275","DOI":"10.1155\/2020\/7024275","article-title":"Self-reported antidepressant drug side effects, medication adherence, and its associated factors among patients diagnosed with depression at the psychiatric hospital of Nepal","volume":"2020","author":"Marasine","year":"2020","journal-title":"Depress. Res. Treat."},{"key":"B27","doi-asserted-by":"publisher","first-page":"616","DOI":"10.1002\/EJI.200940168","article-title":"Signaling by ROS drives inflammasome activation","volume":"40","author":"Martinon","year":"2010","journal-title":"Eur. J. Immunol."},{"key":"B28","doi-asserted-by":"publisher","first-page":"371","DOI":"10.1016\/j.ejphar.2004.07.038","article-title":"The role of monoamines in the actions of established and \u201cnovel\u201d antidepressant agents: A critical review","volume":"500","author":"Millan","year":"2004","journal-title":"Eur. J. Pharmacol."},{"key":"B29","doi-asserted-by":"publisher","first-page":"22","DOI":"10.1038\/nri.2015.5","article-title":"The role of inflammation in depression: From evolutionary imperative to modern treatment target","volume":"16","author":"Miller","year":"2016","journal-title":"Nat. Rev. Immunol."},{"key":"B30","doi-asserted-by":"publisher","first-page":"6493","DOI":"10.1038\/S41598-020-63491-W","article-title":"In-vitro analysis of free radical scavenging activities and suppression of LPS-induced ROS production in macrophage cells by Solanum sisymbriifolium extracts","volume":"10","author":"More","year":"2020","journal-title":"Sci. Rep."},{"key":"B31","doi-asserted-by":"publisher","first-page":"622","DOI":"10.2174\/138920008785821738","article-title":"Chronic immune stimulation correlates with reduced phenylalanine turnover","volume":"9","author":"Neurauter","year":"2008","journal-title":"Curr. Drug Metab."},{"key":"B32","doi-asserted-by":"publisher","first-page":"7709","DOI":"10.1007\/s11033-020-05845-1","article-title":"d-Ribose\u2013l-cysteine exhibits adaptogenic-like activity through inhibition of oxido-inflammatory responses and increased neuronal caspase-3 activity in mice exposed to unpredictable chronic mild stress","volume":"47","author":"Okoh","year":"2020","journal-title":"Mol. Biol. Rep."},{"key":"B33","first-page":"816","article-title":"Role of free radicals in stress-induced neurobehavioural changes in rats","volume":"44","author":"Pal","year":"2006","journal-title":"Indian J. Exp. Biol."},{"key":"B34","doi-asserted-by":"publisher","first-page":"90","DOI":"10.1016\/J.BBI.2014.04.007","article-title":"Microglial NLRP3 inflammasome activation mediates IL-1\u03b2-related inflammation in prefrontal cortex of depressive rats","volume":"41","author":"Pan","year":"2014","journal-title":"Brain, Behav. Immun."},{"key":"B35","doi-asserted-by":"publisher","first-page":"354","DOI":"10.1016\/0006-3223(92)90039-3","article-title":"Low plasma \u03b3-aminobutyric acid levels in male patients with depression","volume":"32","author":"Petty","year":"1992","journal-title":"Biol. Psychiatry"},{"key":"B36","doi-asserted-by":"publisher","first-page":"2977","DOI":"10.1016\/j.bbamcr.2016.09.012","article-title":"Activation of apoptosis signalling pathways by reactive oxygen species","volume":"1863","author":"Redza-Dutordoir","year":"2016","journal-title":"Biochimica Biophysica Acta (BBA) - Mol. Cell Res."},{"key":"B37","doi-asserted-by":"publisher","first-page":"2407","DOI":"10.1007\/S12035-020-02227-3","article-title":"LPS preconditioning attenuates apoptosis mechanism by inhibiting NF-\u03baB and caspase-3 activity: TLR4 pre-activation in the signaling pathway of LPS-induced neuroprotection","volume":"58","author":"Sangaran","year":"2021","journal-title":"Mol. Neurobiol."},{"key":"B38","doi-asserted-by":"publisher","first-page":"1700","DOI":"10.1016\/S0140-6736(21)02143-7","article-title":"Global prevalence and burden of depressive and anxiety disorders in 204 countries and territories in 2020 due to the COVID-19 pandemic","volume":"398","author":"Santomauro","year":"2021","journal-title":"Lancet"},{"key":"B39","doi-asserted-by":"publisher","first-page":"821","DOI":"10.1016\/J.CELL.2010.01.040","article-title":"The inflammasomes","volume":"140","author":"Schroder","year":"2010","journal-title":"Cell"},{"key":"B40","doi-asserted-by":"publisher","first-page":"774","DOI":"10.1037\/A0035302","article-title":"From stress to inflammation and major depressive disorder: A social signal transduction theory of depression","volume":"140","author":"Slavich","year":"2014","journal-title":"Psychol. Bull."},{"key":"B41","doi-asserted-by":"publisher","first-page":"108876","DOI":"10.1016\/J.CBI.2019.108876","article-title":"4-Methylesculetin, a natural coumarin with intestinal anti-inflammatory activity, elicits a glutathione antioxidant response by different mechanisms","volume":"315","author":"Tanimoto","year":"2020","journal-title":"Chemico-Biological Interact."},{"key":"B42","doi-asserted-by":"publisher","first-page":"1495","DOI":"10.1021\/ACSCHEMNEURO.0C00156","article-title":"Astragalin exerted antidepressant-like action through SIRT1 signaling modulated NLRP3 inflammasome deactivation","volume":"11","author":"Tong","year":"2020","journal-title":"ACS Chem. Neurosci."},{"key":"B43","doi-asserted-by":"publisher","first-page":"939","DOI":"10.1046\/J.1471-4159.2003.02242.X","article-title":"Role of reactive oxygen species in LPS-induced production of prostaglandin E2 in microglia","volume":"88","author":"Wang","year":"2004","journal-title":"J. Neurochem."},{"key":"B51","year":"2022"},{"key":"B52","year":"2023"},{"key":"B44","doi-asserted-by":"publisher","first-page":"76","DOI":"10.1016\/J.CBI.2011.11.004","article-title":"Suppression of TNBS-induced colitis in rats by 4-methylesculetin, a natural coumarin: Comparison with prednisolone and sulphasalazine","volume":"195","author":"Witaicenis","year":"2012","journal-title":"Chemico-Biological Interact."},{"key":"B45","doi-asserted-by":"publisher","first-page":"211","DOI":"10.1016\/J.CBI.2010.03.045","article-title":"Intestinal anti-inflammatory activity of esculetin and 4-methylesculetin in the trinitrobenzenesulphonic acid model of rat colitis","volume":"186","author":"Witaicenis","year":"2010","journal-title":"Chemico-Biological Interact."},{"key":"B46","doi-asserted-by":"publisher","first-page":"175","DOI":"10.1016\/J.BBI.2016.02.022","article-title":"NLRP3 inflammasome activation mediates estrogen deficiency-induced depression- and anxiety-like behavior and hippocampal inflammation in mice","volume":"56","author":"Xu","year":"2016","journal-title":"Brain, Behav. Immun."},{"key":"B47","doi-asserted-by":"publisher","first-page":"119","DOI":"10.1111\/CNS.12170","article-title":"Involvement of inflammasome activation in lipopolysaccharide-induced mice depressive-like behaviors","volume":"20","author":"Zhang","year":"2014","journal-title":"CNS Neurosci. Ther."},{"key":"B48","doi-asserted-by":"publisher","first-page":"211","DOI":"10.3389\/FIMMU.2020.00211","article-title":"NLRP3 inflammasome-A key player in antiviral responses","volume":"11","author":"Zhao","year":"2020","journal-title":"Front. Immunol."},{"key":"B49","doi-asserted-by":"publisher","first-page":"494","DOI":"10.1016\/J.BBR.2017.05.064","article-title":"Behavioral, inflammatory and neurochemical disturbances in LPS and UCMS-induced mouse models of depression","volume":"364","author":"Zhao","year":"2019","journal-title":"Behav. Brain Res."},{"key":"B50","doi-asserted-by":"publisher","first-page":"2510","DOI":"10.1038\/npp.2010.116","article-title":"Interleukin-1 receptor activation by systemic lipopolysaccharide induces behavioral despair linked to MAPK regulation of CNS serotonin transporters","volume":"35","author":"Zhu","year":"2010","journal-title":"Neuropsychopharmacology"}],"container-title":["Frontiers in Pharmacology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphar.2023.1120508\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,2,23]],"date-time":"2023-02-23T04:49:52Z","timestamp":1677127792000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphar.2023.1120508\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,2,23]]},"references-count":52,"alternative-id":["10.3389\/fphar.2023.1120508"],"URL":"https:\/\/doi.org\/10.3389\/fphar.2023.1120508","relation":{},"ISSN":["1663-9812"],"issn-type":[{"value":"1663-9812","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,2,23]]},"article-number":"1120508"}}