{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,23]],"date-time":"2026-04-23T05:05:03Z","timestamp":1776920703142,"version":"3.51.2"},"reference-count":49,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2022,2,25]],"date-time":"2022-02-25T00:00:00Z","timestamp":1645747200000},"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>Monoamine-based antidepressants can prophylactically protect against stress-induced gastric ulcers. Although the central nucleus of amygdala (CeA) has been shown to modulate the severity of stress ulcers, little is known about the molecular mechanisms underlying the gastroprotective effect of this kind of drugs. Here, we first used proton magnetic resonance spectroscopy, a non-invasive tool, to explore the change of neurometabolites of the CeA of rats pretreated with the duloxetine of selective serotonin-norepinephrine reuptake inhibitors during 6\u00a0h of water-immersion restraint stress (WIRS). Duloxetine decreased <jats:bold>N-acetyl-aspartate\/creatine ratio (NAA\/creatine)<\/jats:bold> in CeA after WIRS, which was paralleled by the amelioration of gastric lesions. Meanwhile, the gastric ulcer index was negatively correlated with reduced NAA\/creatine. Furthermore, the intra-CeA infusion of NAA aggravated WIRS-induced gastric mucosa damage, which suggested the crucial role of reduced NAA. Western blotting was performed to identify the specific enzymes responsible for the change of the contents of NAA at 0.5\u00a0h\/3\u00a0h\/6\u00a0h after WIRS, considering the preventative gastric protection of duloxetine. The NAA-catabolizing enzyme aspartoacylase (ASPA) was the only enzyme downregulated by 0.5 h WIRS and upregulated by duloxetine. Moreover, overexpressing ASPA in CeA alleviated stress ulcers. Additionally, all of the other three monoamine-based antidepressants, the fluoxetine of selective serotonin reuptake inhibitors, the amitriptyline of tricyclic agents, and the moclobemide of MAOs, increased ASPA expression in CeA. Together, these results indicate that increasing ASPA to hydrolyze NAA in CeA is a common mechanism of gastroprotective effects against stress exerted by monoamine-based antidepressants, and ASPA is a shared target more than monoamine regulation for this kind of drugs.<\/jats:p>","DOI":"10.3389\/fphar.2022.823291","type":"journal-article","created":{"date-parts":[[2022,2,25]],"date-time":"2022-02-25T09:14:38Z","timestamp":1645780478000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":2,"title":["Increasing Aspartoacylase in the Central Amygdala: The Common Mechanism of Gastroprotective Effects of Monoamine-Based Antidepressants Against Stress"],"prefix":"10.3389","volume":"13","author":[{"given":"Kaiyun","family":"Yao","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Linyu","family":"Cao","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hongwan","family":"Ding","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yinge","family":"Gao","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tiegang","family":"Li","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Guibin","family":"Wang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jianjun","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2022,2,25]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"887","DOI":"10.1016\/0896-6273(88)90136-5","article-title":"The Neuronal Mineralocorticoid Receptor as a Mediator of Glucocorticoid Response","volume":"1","author":"Arriza","year":"1988","journal-title":"Neuron"},{"key":"B2","doi-asserted-by":"publisher","first-page":"98","DOI":"10.1038\/nrgastro.2014.235","article-title":"Stress-related Mucosal Disease in the Critically Ill Patient","volume":"12","author":"Bardou","year":"2015","journal-title":"Nat. Rev. Gastroenterol. Hepatol."},{"key":"B3","doi-asserted-by":"publisher","first-page":"47","DOI":"10.1385\/JMN:13:1-2:47","article-title":"Expression of Aspartoacylase Activity in Cultured Rat Macroglial Cells Is Limited to Oligodendrocytes","volume":"13","author":"Baslow","year":"1999","journal-title":"J. Mol. Neurosci."},{"key":"B4","doi-asserted-by":"publisher","first-page":"29156","DOI":"10.1074\/jbc.M110.111765","article-title":"Molecular Characterization of N-Acetylaspartylglutamate Synthetase","volume":"285","author":"Becker","year":"2010","journal-title":"J. Biol. Chem."},{"key":"B5","doi-asserted-by":"publisher","first-page":"78","DOI":"10.24869\/psyd.2020.78","article-title":"Co-Morbidity between Major Depression and Schizophrenia: Prevalence and Clinical Characteristics","volume":"32","author":"Bener","year":"2020","journal-title":"Psychiatr. Danub"},{"key":"B6","doi-asserted-by":"publisher","first-page":"332","DOI":"10.1111\/j.1440-1746.2004.03508.x","article-title":"Stress and the Gastrointestinal Tract","volume":"20","author":"Bhatia","year":"2005","journal-title":"J. Gastroenterol. Hepatol."},{"key":"B7","doi-asserted-by":"publisher","first-page":"173058","DOI":"10.1016\/j.ejphar.2020.173058","article-title":"DUOX2, a Common Modulator in Preventive Effects of Monoamine-Based Antidepressants on Water Immersion Restraint Stress- and Indomethacin- Induced Gastric Mucosal Damage","volume":"876","author":"Cao","year":"2020","journal-title":"Eur. J. Pharmacol."},{"key":"B8","doi-asserted-by":"publisher","first-page":"e12475","DOI":"10.1111\/gbb.12475","article-title":"Oligodendrocyte Gene Expression Is Reduced by and Influences Effects of Chronic Social Stress in Mice","volume":"18","author":"Cathomas","year":"2019","journal-title":"Genes Brain Behav."},{"key":"B9","doi-asserted-by":"publisher","first-page":"60","DOI":"10.1002\/bies.201400127","article-title":"The Emerging Functions of Oligodendrocytes in Regulating Neuronal Network Behaviour","volume":"37","author":"de Hoz","year":"2015","journal-title":"Bioessays"},{"key":"B10","doi-asserted-by":"publisher","first-page":"864","DOI":"10.1016\/j.cell.2019.10.001","article-title":"Stress-Induced Metabolic Disorder in Peripheral CD4+ T Cells Leads to Anxiety-like Behavior","volume":"179","author":"Fan","year":"2019","journal-title":"Cell"},{"key":"B11","doi-asserted-by":"publisher","first-page":"474433","DOI":"10.1038\/sj.mp.4001031","article-title":"Marked Suppression of Gastric Ulcerogenesis and Intestinal Responses to Stress by a Novel Class of Drugs","volume":"7","author":"Gabry","year":"2002","journal-title":"Mol. Psychiatry"},{"key":"B12","doi-asserted-by":"publisher","first-page":"e1009539","DOI":"10.1371\/journal.pgen.1009539","article-title":"Mapping the Degradation Pathway of a Disease-Linked Aspartoacylase Variant","volume":"17","author":"Gersing","year":"2021","journal-title":"Plos Genet."},{"key":"B13","doi-asserted-by":"publisher","first-page":"253","DOI":"10.1007\/s40199-020-00336-x","article-title":"A New Sesquiterpenoid from the Shoots of Iranian Daphne Mucronata Royle with Selective Inhibition of STAT3 and Smad3\/4 Cancer-Related Signaling Pathways","volume":"28","author":"Ghanadian","year":"2020","journal-title":"Daru"},{"key":"B14","doi-asserted-by":"publisher","first-page":"217","DOI":"10.1016\/0278-5846(92)90073-n","article-title":"Central Dopamine Involvement in Experimental Gastrointestinal Injury","volume":"16","author":"Glavin","year":"1992","journal-title":"Prog. Neuropsychopharmacol. Biol. Psychiatry"},{"key":"B15","doi-asserted-by":"publisher","first-page":"1106","DOI":"10.1056\/NEJM199604253341707","article-title":"The Enteric Nervous System","volume":"334","author":"Goyal","year":"1996","journal-title":"N. Engl. J. Med."},{"key":"B16","doi-asserted-by":"publisher","first-page":"105","DOI":"10.24869\/psyd.2020.105","article-title":"Evaluation of Eating Attitudes, Anger and Impulsivity in Atypical and Non-atypical Depression and Assessment of Comorbidity of Binge Eating","volume":"32","author":"G\u00fcng\u00f6r","year":"2020","journal-title":"Psychiatr. Danub"},{"key":"B17","doi-asserted-by":"publisher","first-page":"1067","DOI":"10.1007\/s12264-018-0282-y","article-title":"Altered Neuronal Activity in the Central Nucleus of the Amygdala Induced by Restraint Water-Immersion Stress in Rats","volume":"34","author":"He","year":"2018","journal-title":"Neurosci. Bull."},{"key":"B18","doi-asserted-by":"publisher","first-page":"2336","DOI":"10.1093\/cercor\/bhr313","article-title":"Corticosteroid Induced Decoupling of the Amygdala in Men","volume":"22","author":"Henckens","year":"20121991","journal-title":"Cereb. Cortex"},{"key":"B19","doi-asserted-by":"publisher","first-page":"1633","DOI":"10.1007\/BF01296409","article-title":"The Amygdala. Emotions and Gut Functions","volume":"36","author":"Henke","year":"1991","journal-title":"Dig. Dis. Sci."},{"key":"B20","doi-asserted-by":"publisher","first-page":"143","DOI":"10.1016\/s0149-7634(88)80006-x","article-title":"Recent Studies of the central Nucleus of the Amygdala and Stress Ulcers","volume":"12","author":"Henke","year":"1988","journal-title":"Neurosci. Biobehav Rev."},{"key":"B21","doi-asserted-by":"publisher","first-page":"682","DOI":"10.1111\/j.1471-4159.2006.04341.x","article-title":"Biochemical Characterization of Human Glutamate Carboxypeptidase III","volume":"101","author":"Hlouchov\u00e1","year":"2007","journal-title":"J. Neurochem."},{"key":"B22","doi-asserted-by":"publisher","first-page":"589582","DOI":"10.3389\/fncel.2020.589582","article-title":"Lactate Transporters Mediate Glia-Neuron Metabolic Crosstalk in Homeostasis and Disease","volume":"14","author":"Jha","year":"2020","journal-title":"Front Cel Neurosci"},{"key":"B23","doi-asserted-by":"publisher","first-page":"46","DOI":"10.1016\/j.ejphar.2012.06.041","article-title":"Evaluation of the Anti-ulcerogenic Activity of the Antidepressants Duloxetine, Amitriptyline, Fluoxetine and Mirtazapine in Different Models of Experimental Gastric Ulcer in Rats","volume":"691","author":"Ji","year":"2012","journal-title":"Eur. J. Pharmacol."},{"key":"B24","doi-asserted-by":"publisher","first-page":"e53976","DOI":"10.3791\/53976","article-title":"Combining Double Fluorescence In Situ Hybridization with Immunolabelling for Detection of the Expression of Three Genes in Mouse Brain Sections","volume":"109","author":"Jolly","year":"2016","journal-title":"J. Vis. Exp."},{"key":"B25","doi-asserted-by":"publisher","first-page":"195","DOI":"10.1515\/jbcpp-2018-0067","article-title":"Selective Serotonin Reuptake Inhibitor Fluvoxamine Ameliorates Stress- and NSAID-Induced Peptic Ulcer Possibly by Involving Hsp70","volume":"30","author":"Khotib","year":"2019","journal-title":"J. Basic Clin. Physiol. Pharmacol."},{"key":"B26","first-page":"591","article-title":"Stress and the Gut: Pathophysiology, Clinical Consequences, Diagnostic Approach and Treatment Options","volume":"62","author":"Konturek","year":"2011","journal-title":"J. Physiol. Pharmacol."},{"key":"B27","article-title":"Application of Novel Therapeutic Agents for CNS Injury: NAAG Peptidase Inhibitors","volume-title":"Brain Neurotrauma: Molecular, Neuropsychological, and Rehabilitation Aspects","author":"Lyeth","year":"2015"},{"key":"B28","doi-asserted-by":"publisher","first-page":"199","DOI":"10.1007\/7854_2011_197","article-title":"MR Spectroscopic Studies of the Brain in Psychiatric Disorders","volume":"11","author":"Maddock","year":"2012","journal-title":"Curr. Top. Behav. Neurosci."},{"key":"B29","doi-asserted-by":"publisher","first-page":"5221","DOI":"10.1073\/pnas.0409184102","article-title":"Defective N-Acetylaspartate Catabolism Reduces Brain Acetate Levels and Myelin Lipid Synthesis in Canavan's Disease","volume":"102","author":"Madhavarao","year":"2005","journal-title":"Proc. Natl. Acad. Sci. U S A."},{"key":"B30","doi-asserted-by":"publisher","first-page":"211","DOI":"10.1369\/0022155413517700","article-title":"Distribution of Corticosteroid Receptors in Mature Oligodendrocytes and Oligodendrocyte Progenitors of the Adult Mouse Brain","volume":"62","author":"Matsusue","year":"2014","journal-title":"J. Histochem. Cytochem."},{"key":"B31","doi-asserted-by":"publisher","first-page":"174","DOI":"10.1016\/j.ejphar.2007.11.071","article-title":"Central Effects of Stress Hormones in Health and Disease: Understanding the Protective and Damaging Effects of Stress and Stress Mediators","volume":"583","author":"McEwen","year":"2008","journal-title":"Eur. J. Pharmacol."},{"key":"B32","first-page":"3752","article-title":"In Silico interactions between Curcumin Derivatives and Monoamine Oxidase-A Enzyme","volume":"12","author":"Mirzaei","year":"2022","journal-title":"Biointerface Res. Appl. Chem."},{"key":"B33","doi-asserted-by":"publisher","first-page":"1414","DOI":"10.1002\/glia.21186","article-title":"Extensive Aspartoacylase Expression in the Rat central Nervous System","volume":"59","author":"Moffett","year":"2011","journal-title":"Glia"},{"key":"B34","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/s0003-9861(03)00055-9","article-title":"Purification and Preliminary Characterization of Brain Aspartoacylase","volume":"413","author":"Moore","year":"2003","journal-title":"Arch. Biochem. Biophys."},{"key":"B35","doi-asserted-by":"publisher","first-page":"1043","DOI":"10.1016\/0031-9384(93)90357-l","article-title":"Effects of Amygdaloid Lesions on Gastric Erosion Formation during Exposure to Activity-Stress","volume":"53","author":"Morrow","year":"1993","journal-title":"Physiol. Behav."},{"key":"B36","doi-asserted-by":"publisher","first-page":"490","DOI":"10.1111\/j.1471-4159.2011.07338.x","article-title":"Advances in Understanding the Peptide Neurotransmitter NAAG and Appearance of a New Member of the NAAG Neuropeptide Family","volume":"118","author":"Neale","year":"2011","journal-title":"J. Neurochem."},{"key":"B37","doi-asserted-by":"publisher","first-page":"101722","DOI":"10.1016\/j.pneurobio.2019.101722","article-title":"N-acetylaspartylglutamate (NAAG) and Glutamate Carboxypeptidase II: An Abundant Peptide Neurotransmitter-Enzyme System with Multiple Clinical Applications","volume":"184","author":"Neale","year":"2020","journal-title":"Prog. Neurobiol."},{"key":"B38","doi-asserted-by":"publisher","first-page":"1659","DOI":"10.1016\/j.euroneuro.2014.06.004","article-title":"N-acetyl-aspartate (NAA) as a Correlate of Pharmacological Treatment in Psychiatric Disorders: a Systematic Review","volume":"24","author":"Paslakis","year":"2014","journal-title":"Eur. Neuropsychopharmacol."},{"key":"B39","doi-asserted-by":"publisher","first-page":"539","DOI":"10.1042\/bj1840539","article-title":"Synthesis of N-Acetyl-L-Aspartate by Rat Brain Mitochondria and its Involvement in Mitochondrial\/cytosolic Carbon Transport","volume":"184","author":"Patel","year":"1979","journal-title":"Biochem. J."},{"key":"B40","doi-asserted-by":"publisher","first-page":"144","DOI":"10.1016\/j.ab.2016.11.007","article-title":"Creatine in the central Nervous System: From Magnetic Resonance Spectroscopy to Creatine Deficiencies","volume":"529","author":"Rackayova","year":"2017","journal-title":"Anal. Biochem."},{"key":"B41","doi-asserted-by":"publisher","first-page":"179","DOI":"10.1016\/0166-4328(90)90172-b","article-title":"Enkephalin-dopamine Interactions in the central Amygdalar Nucleus during Gastric Stress Ulcer Formation in Rats","volume":"36","author":"Ray","year":"1990","journal-title":"Behav. Brain Res."},{"key":"B42","doi-asserted-by":"publisher","first-page":"331","DOI":"10.1016\/0304-3940(90)90869-b","article-title":"Noradrenergic Mechanisms in the central Amygdalar Nucleus and Gastric Stress Ulcer Formation in Rats","volume":"110","author":"Ray","year":"1990","journal-title":"Neurosci. Lett."},{"key":"B43","doi-asserted-by":"publisher","first-page":"11","DOI":"10.1016\/0167-0115(91)90249-g","article-title":"TRH-enkephalin Interactions in the Amygdaloid Complex during Gastric Stress Ulcer Formation in Rats","volume":"35","author":"Ray","year":"1991","journal-title":"Regul. Pept."},{"key":"B44","doi-asserted-by":"publisher","first-page":"311","DOI":"10.1046\/j.1472-8206.2002.00092.x","article-title":"Effect of Amitriptyline on Gastric Ulceration","volume":"16","author":"Sen","year":"2002","journal-title":"Fundam. Clin. Pharmacol."},{"key":"B45","doi-asserted-by":"publisher","first-page":"1011","DOI":"10.1176\/appi.ajp.2009.08121760","article-title":"A Molecular Signature of Depression in the Amygdala","volume":"166","author":"Sibille","year":"2009","journal-title":"Am. J. Psychiatry"},{"key":"B46","doi-asserted-by":"publisher","first-page":"201","DOI":"10.1007\/s11033-007-9167-2","article-title":"Upregulation of N-Acetylaspartic Acid Alters Inflammation, Transcription and Contractile Associated Protein Levels in the Stomach and Smooth Muscle Contractility","volume":"36","author":"Surendran","year":"2009","journal-title":"Mol. Biol. Rep."},{"key":"B47","doi-asserted-by":"publisher","first-page":"27","DOI":"10.1016\/s0091-3057(97)00312-2","article-title":"Expression of Aggression Attenuates Both Stress-Induced Gastric Ulcer Formation and Increases in Noradrenaline Release in the Rat Amygdala Assessed by Intracerebral Microdialysis","volume":"59","author":"Tanaka","year":"1998","journal-title":"Pharmacol. Biochem. Behav."},{"key":"B48","doi-asserted-by":"publisher","first-page":"102134","DOI":"10.1016\/j.artmed.2021.102134","article-title":"Network Differentiation: A Computational Method of Pathogenesis Diagnosis in Traditional Chinese Medicine Based on Systems Science","volume":"118","author":"Xu","year":"2021","journal-title":"Artif. Intell. Med."},{"key":"B49","doi-asserted-by":"publisher","first-page":"203","DOI":"10.1016\/j.apsb.2020.07.005","article-title":"Discovery of Thiosemicarbazone Derivatives as Effective New Delhi Metallo-\u03b2-Lactamase-1 (NDM-1) Inhibitors against NDM-1 Producing Clinical Isolates","volume":"11","author":"Zhao","year":"2021","journal-title":"Acta Pharm. Sin B"}],"container-title":["Frontiers in Pharmacology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphar.2022.823291\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,2,25]],"date-time":"2022-02-25T09:14:42Z","timestamp":1645780482000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphar.2022.823291\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,2,25]]},"references-count":49,"alternative-id":["10.3389\/fphar.2022.823291"],"URL":"https:\/\/doi.org\/10.3389\/fphar.2022.823291","relation":{},"ISSN":["1663-9812"],"issn-type":[{"value":"1663-9812","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,2,25]]},"article-number":"823291"}}