{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,4]],"date-time":"2026-05-04T10:25:22Z","timestamp":1777890322401,"version":"3.51.4"},"reference-count":55,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,5,1]],"date-time":"2026-05-01T00:00:00Z","timestamp":1777593600000},"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. Cell Dev. Biol."],"abstract":"<jats:p>\n                    Parkinson\u2019s disease (PD) is characterized by profound metabolic disturbances in the brain, yet how these alterations vary across brain regions and respond to neuroprotective intervention remains poorly understood. Here, we applied airflow-assisted desorption electrospray ionization mass spectrometry imaging (AFADESI-MSI) to map spatial metabolic changes in whole brains from 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD rats and to define the\n                    <jats:italic>in situ<\/jats:italic>\n                    metabolic effects of nicotine. Spatial metabolomics revealed marked region-dependent metabolic disruption in the PD brain and showed that nicotine broadly reversed the MPTP-induced shift in metabolic trajectories. In particular, nicotine restored dopamine-related metabolites in the striatum and midbrain, normalized \u03b3-aminobutyric acid and serotonin in the hippocampus and thalamus, and alleviated biochemical features of mitochondrial stress by reducing AMP accumulation and restoring glutathione levels. Pathway analysis further identified glycerophospholipid metabolism as a shared regulatory axis across multiple brain regions, suggesting that recovery of membrane lipid homeostasis is a central component of nicotine-mediated neuroprotection. Together, these findings indicate that nicotine exerts spatially coordinated neuroprotective effects in PD by remodeling neurotransmitter balance, improving redox and energy homeostasis, and repairing membrane lipid metabolism. More broadly, this study highlights the value of spatial metabolomics for revealing brain-region-specific metabolic mechanisms of neurodegeneration and drug action.\n                  <\/jats:p>","DOI":"10.3389\/fcell.2026.1818201","type":"journal-article","created":{"date-parts":[[2026,5,1]],"date-time":"2026-05-01T05:35:28Z","timestamp":1777613728000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Exploring In situ neuroprotective mechanisms of nicotine in an MPTP-Induced Parkinson\u2019s disease rat model using spatial metabolomics"],"prefix":"10.3389","volume":"14","author":[{"given":"Lutao","family":"Xu","sequence":"first","affiliation":[{"name":"Beijing Life Science Academy","place":["Beijing, China"]},{"name":"Key Laboratory of Tobacco Biological Effects, China National Tobacco Quality Supervision & Test Center","place":["Zhengzhou, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Qian","family":"Li","sequence":"additional","affiliation":[{"name":"Beijing Life Science Academy","place":["Beijing, China"]},{"name":"Key Laboratory of Tobacco Biological Effects, China National Tobacco Quality Supervision & Test Center","place":["Zhengzhou, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mingyu","family":"Zhu","sequence":"additional","affiliation":[{"name":"Beijing Life Science Academy","place":["Beijing, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gaoge","family":"Wang","sequence":"additional","affiliation":[{"name":"Beijing Life Science Academy","place":["Beijing, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hongjuan","family":"Wang","sequence":"additional","affiliation":[{"name":"Key Laboratory of Tobacco Biological Effects, China National Tobacco Quality Supervision & Test Center","place":["Zhengzhou, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shulei","family":"Han","sequence":"additional","affiliation":[{"name":"Key Laboratory of Tobacco Biological Effects, China National Tobacco Quality Supervision & Test Center","place":["Zhengzhou, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yaning","family":"Fu","sequence":"additional","affiliation":[{"name":"Beijing Life Science Academy","place":["Beijing, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Huan","family":"Chen","sequence":"additional","affiliation":[{"name":"Beijing Life Science Academy","place":["Beijing, China"]},{"name":"Key Laboratory of Tobacco Biological Effects, China National Tobacco Quality Supervision & Test Center","place":["Zhengzhou, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hongwei","family":"Hou","sequence":"additional","affiliation":[{"name":"Beijing Life Science Academy","place":["Beijing, China"]},{"name":"Key Laboratory of Tobacco Biological Effects, China National Tobacco Quality Supervision & Test Center","place":["Zhengzhou, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2026,5,1]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"42","DOI":"10.1002\/mdc3.13344","article-title":"MPTP parkinsonism and implications for understanding parkinson\u2019s disease","volume":"9","author":"AlShimemeri","year":"2022","journal-title":"Mov. Disord. Clin. Pract."},{"key":"B2","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/j.nbd.2019.04.017","article-title":"Nicotine prevents alpha-synuclein accumulation in mouse and human iPSC-derived dopaminergic neurons through activation of the dopamine D3-acetylcholine nicotinic receptor heteromer","volume":"129","author":"Bono","year":"2019","journal-title":"Neurobiol. Dis."},{"key":"B3","doi-asserted-by":"publisher","first-page":"16","DOI":"10.1038\/s41467-025-57765-y","article-title":"Metabolomics strategy for diagnosing urinary tract infections","volume":"16","author":"Chan","year":"2025","journal-title":"Nat. Commun."},{"key":"B4","doi-asserted-by":"publisher","first-page":"156412","DOI":"10.1016\/j.phymed.2025.156412","article-title":"Spatial metabolic modulation in vascular dementia by erigeron breviscapus injection using ambient mass spectrometry imaging","volume":"138","author":"Cheng","year":"2025","journal-title":"Phytomedicine"},{"key":"B5","doi-asserted-by":"publisher","first-page":"4373","DOI":"10.1038\/s41467-025-59487-7","article-title":"Spatial mapping of the brain metabolome lipidome and glycome","volume":"16","author":"Clarke","year":"2025","journal-title":"Nat. Commun."},{"key":"B6","doi-asserted-by":"publisher","first-page":"a041610","DOI":"10.1101\/cshperspect.a041610","article-title":"Neuropathology of parkinson\u2019s disease and parkinsonism","author":"Dickson","year":"2025","journal-title":"Cold Spring Harb. Perspect. Med."},{"key":"B7","doi-asserted-by":"publisher","first-page":"694","DOI":"10.1016\/j.jpha.2023.04.003","article-title":"Dissecting the brain with spatially resolved multi-omics","volume":"13","author":"Fangma","year":"2023","journal-title":"J. Pharm. Anal."},{"key":"B8","doi-asserted-by":"publisher","first-page":"105933","DOI":"10.1016\/j.nbd.2022.105933","article-title":"Longitudinal spatial mapping of lipid metabolites reveals pre-symptomatic changes in the hippocampi of huntington\u2019s disease transgenic mice","volume":"176","author":"Farzana","year":"2023","journal-title":"Neurobiol. Dis."},{"key":"B9","doi-asserted-by":"publisher","first-page":"eabe5948","DOI":"10.1126\/sciadv.abe5948","article-title":"Mass spectrometry imaging identifies abnormally elevated brain l -DOPA levels and extrastriatal monoaminergic dysregulation in l -DOPA\u2013induced dyskinesia","volume":"7","author":"Fridjonsdottir","year":"2021","journal-title":"Sci. Adv."},{"key":"B10","doi-asserted-by":"publisher","first-page":"101210","DOI":"10.1016\/j.jpha.2025.101210","article-title":"Disorder of phospholipid metabolism in the renal cortex and medulla contributes to acute tubular necrosis in mice after cantharidin exposure using integrative lipidomics and spatial metabolomics","volume":"15","author":"He","year":"2025","journal-title":"J. Pharm. Anal."},{"key":"B11","doi-asserted-by":"publisher","first-page":"8260","DOI":"10.1038\/s41467-023-43917-5","article-title":"Single-cell spatial metabolomics with cell-type specific protein profiling for tissue systems biology","volume":"14","author":"Hu","year":"2023","journal-title":"Nat. Commun."},{"key":"B12","doi-asserted-by":"publisher","first-page":"613","DOI":"10.1111\/jnc.14468","article-title":"Subventricular zone lipidomic architecture loss in huntington\u2019s disease","volume":"146","author":"Hunter","year":"2018","journal-title":"J. Neurochem."},{"key":"B13","doi-asserted-by":"publisher","first-page":"2158","DOI":"10.1111\/jnc.15325","article-title":"An imaging mass spectrometry atlas of lipids in the human neurologically normal and huntington\u2019s disease caudate nucleus","volume":"157","author":"Hunter","year":"2021","journal-title":"J. Neurochem."},{"key":"B14","doi-asserted-by":"publisher","first-page":"a041641","DOI":"10.1101\/cshperspect.a041641","article-title":"Progression in parkinson\u2019s disease","author":"Irmady","year":"2025","journal-title":"Cold Spring Harb. Perspect. Med."},{"key":"B15","doi-asserted-by":"publisher","first-page":"141","DOI":"10.1038\/nprot.2006.342","article-title":"Protocol for the MPTP mouse model of parkinson\u2019s disease","volume":"2","author":"Jackson-Lewis","year":"2007","journal-title":"Nat. Protoc."},{"key":"B16","doi-asserted-by":"publisher","first-page":"e5008","DOI":"10.1002\/jms.5008","article-title":"Spatial neurolipidomics\u2014MALDI mass spectrometry imaging of lipids in brain pathologies","volume":"59","author":"Jha","year":"2024","journal-title":"J. Mass Spectrom."},{"key":"B17","doi-asserted-by":"publisher","first-page":"117103","DOI":"10.1016\/j.trac.2023.117103","article-title":"A new direction in metabolomics: analysis of the central nervous system based on spatially resolved metabolomics","volume":"165","author":"Jiang","year":"2023","journal-title":"Trends Anal. Chem."},{"key":"B18","doi-asserted-by":"publisher","first-page":"836","DOI":"10.1021\/jasms.2c00336","article-title":"On-tissue chemical derivatization for comprehensive mapping of brain carboxyl and aldehyde metabolites by MALDI\u2013MS imaging","volume":"34","author":"Kaya","year":"","journal-title":"J. Am. Soc. Mass Spectrom."},{"key":"B19","doi-asserted-by":"publisher","first-page":"9","DOI":"10.1038\/s41531-023-00558-1","article-title":"Spatial lipidomics reveals brain region-specific changes of sulfatides in an experimental MPTP parkinson\u2019s disease primate model","volume":"9","author":"Kaya","year":"","journal-title":"npj Parkinson\u2019s Dis."},{"key":"B20","doi-asserted-by":"publisher","first-page":"21","DOI":"10.1186\/s12974-024-03139-y","article-title":"Contribution of CNS and extra-CNS infections to neurodegeneration: a narrative review","volume":"21","author":"Kettunen","year":"2024","journal-title":"J. Neuroinflammation"},{"key":"B21","doi-asserted-by":"publisher","first-page":"1625","DOI":"10.1007\/s12035-015-9103-8","article-title":"Validity of the MPTP-treated mouse as a model for parkinson\u2019s disease","volume":"53","author":"Klemann","year":"2016","journal-title":"Mol. Neurobiol."},{"key":"B22","doi-asserted-by":"publisher","first-page":"1822","DOI":"10.1038\/s41592-023-02034-3","article-title":"Waxholm space atlas of the rat brain: a 3D atlas supporting data analysis and integration","volume":"20","author":"Kleven","year":"2023","journal-title":"Nat. Methods"},{"key":"B23","doi-asserted-by":"publisher","first-page":"r350","DOI":"10.1136\/bmj.r350","article-title":"Projecting parkinson\u2019s disease burden","volume":"388","author":"Kurth","year":"2025","journal-title":"BMJ"},{"key":"B24","doi-asserted-by":"publisher","first-page":"13","DOI":"10.1186\/s40035-024-00430-z","article-title":"Blood\u2013brain barrier alterations and their impact on parkinson\u2019s disease pathogenesis and therapy","volume":"13","author":"Lau","year":"2024","journal-title":"Transl. Neurodegener."},{"key":"B25","doi-asserted-by":"publisher","first-page":"100973","DOI":"10.1016\/j.jpha.2024.100973","article-title":"Pharmacometabolomics and mass spectrometry imaging approach to reveal the neurochemical mechanisms of polygala tenuifolia","volume":"14","author":"Li","year":"2024","journal-title":"J. Pharm. Anal."},{"key":"B26","doi-asserted-by":"publisher","first-page":"S2090123225006599","DOI":"10.1016\/j.jare.2025.08.044","article-title":"Spatial-temporal lipidomics reveals dysregulated lipid metabolism in mouse brain during alzheimer\u2019s disease progression","author":"Li","year":"2025","journal-title":"J. Adv. Res."},{"key":"B27","doi-asserted-by":"publisher","first-page":"1535310","DOI":"10.3389\/fnagi.2025.1535310","article-title":"Significance of nicotine and nicotinic acetylcholine receptors in parkinson\u2019s disease","volume":"17","author":"Lin","year":"2025","journal-title":"Front. Aging Neurosci."},{"key":"B28","doi-asserted-by":"publisher","first-page":"344721","DOI":"10.1016\/j.aca.2025.344721","article-title":"Deciphering the three-dimensional biomolecular distribution in the alzheimer\u2019s disease brain: a multiomic approach integrating immunohistochemistry with MALDI MS imaging","volume":"1379","author":"Lu","year":"2025","journal-title":"Anal. Chim. Acta"},{"key":"B29","doi-asserted-by":"publisher","first-page":"2977","DOI":"10.1021\/ac400009s","article-title":"Air flow-assisted ionization imaging mass spectrometry method for easy whole-body molecular imaging under ambient conditions","volume":"85","author":"Luo","year":"2013","journal-title":"Anal. Chem."},{"key":"B30","doi-asserted-by":"publisher","first-page":"4968","DOI":"10.3390\/cimb46050298","article-title":"Spatial multi-omics in alzheimer\u2019s disease: a multi-dimensional approach to understanding pathology and progression","volume":"46","author":"Ma","year":"2024","journal-title":"Curr. Issues Mol. Biol."},{"key":"B31","doi-asserted-by":"publisher","first-page":"19","DOI":"10.3233\/JPD-2011-11023","article-title":"MPTP mouse models of parkinson\u2019s disease: an update","volume":"1","author":"Meredith","year":"2011","journal-title":"J. Parkinson\u2019s Dis."},{"key":"B32","doi-asserted-by":"publisher","first-page":"422","DOI":"10.17305\/bjbms.2020.5181","article-title":"MPTP-induced mouse model of parkinson\u2019s disease: a promising direction for therapeutic strategies","volume":"21","author":"Mustapha","year":"2021","journal-title":"Bosn. J. Basic Med. Sci."},{"key":"B33","doi-asserted-by":"publisher","first-page":"7","DOI":"10.3389\/fagro.2025.1456015","article-title":"Pedological characterization of soils under tobacco cultivation: insights from sikonge, uyui and tabora districts in tabora region, Tanzania","volume":"7","author":"Mwalembe","year":"2025","journal-title":"Front. Agron."},{"key":"B34","doi-asserted-by":"publisher","first-page":"e5143","DOI":"10.1002\/jms.5143","article-title":"Spatial multiomics toward understanding neurological systems","volume":"60","author":"Neumann","year":"2025","journal-title":"J. Mass Spectrom."},{"key":"B35","doi-asserted-by":"publisher","first-page":"3675","DOI":"10.1038\/s41467-024-48009-6","article-title":"MetaboAnalystR 4.0: a unified LC-MS workflow for global metabolomics","volume":"15","author":"Pang","year":"2024","journal-title":"Nat. Commun."},{"key":"B36","doi-asserted-by":"publisher","first-page":"18","DOI":"10.1186\/s13024-023-00694-5","article-title":"Untargeted serum metabolomics reveals novel metabolite associations and disruptions in amino acid and lipid metabolism in parkinson\u2019s disease","volume":"18","author":"Paul","year":"2023","journal-title":"Mol. Neurodegener."},{"key":"B37","doi-asserted-by":"publisher","first-page":"1021","DOI":"10.1038\/s41592-019-0551-3","article-title":"Comprehensive mapping of neurotransmitter networks by MALDI\u2013MS imaging","volume":"16","author":"Shariatgorji","year":"2019","journal-title":"Nat. Methods"},{"key":"B38","doi-asserted-by":"publisher","first-page":"57","DOI":"10.1016\/j.molbrainres.2004.09.017","article-title":"The MPTP model of parkinson\u2019s disease","volume":"134","author":"Smeyne","year":"2005","journal-title":"Brain Res. Mol. Brain Res."},{"key":"B39","doi-asserted-by":"publisher","first-page":"19001","DOI":"10.1021\/acs.analchem.5c01767","article-title":"To spray or to sublimate: considerations for the matrix application of three common positive ion mode matrices","volume":"97","author":"Spears","year":"2025","journal-title":"Anal. Chem."},{"key":"B40","doi-asserted-by":"publisher","first-page":"754","DOI":"10.1126\/science.373.6556.754-j","article-title":"Accessory proteins and nicotinic receptors","volume":"373","author":"Stern","year":"2021","journal-title":"Science"},{"key":"B41","doi-asserted-by":"publisher","first-page":"2052","DOI":"10.1016\/j.ymthe.2025.03.030","article-title":"Recent developments in gene therapy for parkinson\u2019s disease","volume":"33","author":"Szunyogh","year":"2025","journal-title":"Mol. Ther."},{"key":"B42","doi-asserted-by":"publisher","first-page":"3322","DOI":"10.1021\/acs.jproteome.5b00354","article-title":"Analysis of the human adult urinary metabolome variations with age, body mass index, and gender by implementing a comprehensive workflow for univariate and OPLS statistical analyses","volume":"14","author":"Th\u00e9venot","year":"2015","journal-title":"J. Proteome Res."},{"key":"B43","doi-asserted-by":"publisher","first-page":"18352","DOI":"10.1021\/acs.analchem.3c02900","article-title":"Rapid metabolic profiling of 1 \u03bcL crude cerebrospinal fluid by matrix-assisted laser desorption\/ionization mass spectrometry imaging can differentiate de novo parkinson\u2019s disease","volume":"95","author":"Vallianatou","year":"2023","journal-title":"Anal. Chem."},{"key":"B44","doi-asserted-by":"publisher","first-page":"1046","DOI":"10.1038\/s41587-023-01937-y","article-title":"Spatial multimodal analysis of transcriptomes and metabolomes in tissues","volume":"42","author":"Vicari","year":"2024","journal-title":"Nat. Biotechnol."},{"key":"B45","doi-asserted-by":"publisher","first-page":"2268","DOI":"10.1016\/j.scib.2023.08.047","article-title":"Advances in mass spectrometry-based multi-scale metabolomic methodologies and their applications in biological and clinical investigations","volume":"68","author":"Wang","year":"2023","journal-title":"Sci. Bull."},{"key":"B46","doi-asserted-by":"publisher","first-page":"108230","DOI":"10.1016\/j.cclet.2023.108230","article-title":"Urine biomarkers discovery by metabolomics and machine learning for parkinson\u2019s disease diagnoses","volume":"34","author":"Wang","year":"2023","journal-title":"Chin. Chem. Lett."},{"key":"B47","doi-asserted-by":"publisher","first-page":"109653","DOI":"10.1016\/j.cclet.2024.109653","article-title":"Discovery of plasma biomarkers for parkinson\u2019s disease diagnoses based on metabolomics and lipidomics","volume":"35","author":"Wang","year":"2024","journal-title":"Chin. Chem. Lett."},{"key":"B48","doi-asserted-by":"publisher","first-page":"117713","DOI":"10.1016\/j.trac.2024.117713","article-title":"Frontiers in mass spectrometry-based spatial metabolomics: current applications and challenges in the context of biomedical research","volume":"175","author":"Wheeler","year":"2024","journal-title":"TrAC, Trends Anal. Chem."},{"key":"B49","doi-asserted-by":"publisher","first-page":"199","DOI":"10.1111\/j.1749-6632.2003.tb07477.x","article-title":"Pathophysiology of parkinson\u2019s disease: the MPTP primate model of the human disorder","volume":"991","author":"Wichmann","year":"2003","journal-title":"Ann. N. Y. Acad. Sci."},{"key":"B50","doi-asserted-by":"publisher","first-page":"75","DOI":"10.3389\/fnagi.2020.00075","article-title":"Brain-region specific metabolic abnormalities in parkinson\u2019s disease and levodopa-induced dyskinesia","volume":"12","author":"Yang","year":"2020","journal-title":"Front. Aging Neurosci."},{"key":"B51","doi-asserted-by":"publisher","first-page":"3127","DOI":"10.1021\/acschemneuro.5c00144","article-title":"Multimodal nano-DESI mass spectrometry imaging reveals phospholipids accumulation in and around amyloid plaques in alzheimer\u2019s disease","volume":"16","author":"Yang","year":"2025","journal-title":"ACS Chem. Neurosci."},{"key":"B52","doi-asserted-by":"publisher","first-page":"155881","DOI":"10.1016\/j.phymed.2024.155881","article-title":"Efficacy of astragalus membranaceus\u2013carthamus tinctorius in cerebral ischemia\/reperfusion injury: insights from metabolomics and mass spectrometry imaging","volume":"133","author":"Zhao","year":"2024","journal-title":"Phytomedicine"},{"key":"B53","doi-asserted-by":"publisher","first-page":"290","DOI":"10.1007\/s11011-025-01673-z","article-title":"Spatial metabolomics reveals the effects of acanthopanax senticosus on region-specific alterations in neurotransmitters and metabolites levels in the brains of \u03b1-syn transgenic parkinson\u2019s disease model mice","volume":"40","author":"Zheng","year":"2025","journal-title":"Metab. Brain Dis."},{"key":"B54","doi-asserted-by":"publisher","first-page":"9","DOI":"10.1002\/advs.202204468","article-title":"Spatial regulation control of oxygen metabolic consumption in mouse brain","volume":"9","author":"Zhou","year":"2022","journal-title":"Adv. Sci."},{"key":"B55","doi-asserted-by":"publisher","first-page":"7286","DOI":"10.1021\/acs.analchem.2c00557","article-title":"An organ-specific metabolite annotation approach for ambient mass spectrometry imaging reveals spatial metabolic alterations of a whole mouse body","volume":"94","author":"Zhu","year":"2022","journal-title":"Anal. Chem."}],"container-title":["Frontiers in Cell and Developmental Biology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fcell.2026.1818201\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,5,1]],"date-time":"2026-05-01T05:35:30Z","timestamp":1777613730000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fcell.2026.1818201\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,5,1]]},"references-count":55,"alternative-id":["10.3389\/fcell.2026.1818201"],"URL":"https:\/\/doi.org\/10.3389\/fcell.2026.1818201","relation":{},"ISSN":["2296-634X"],"issn-type":[{"value":"2296-634X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,5,1]]},"article-number":"1818201"}}