{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,28]],"date-time":"2026-08-28T21:25:44Z","timestamp":1787952344614,"version":"build-2784847793"},"reference-count":79,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2024,3,24]],"date-time":"2024-03-24T00:00:00Z","timestamp":1711238400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001807","name":"Funda\u00e7\u00e3o de Amparo a Pesquisa do Estado de S\u00e3o Paulo","doi-asserted-by":"publisher","award":["2017-22574-0"],"award-info":[{"award-number":["2017-22574-0"]}],"id":[{"id":"10.13039\/501100001807","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001807","name":"Funda\u00e7\u00e3o de Amparo a Pesquisa do Estado de S\u00e3o Paulo","doi-asserted-by":"publisher","award":["001"],"award-info":[{"award-number":["001"]}],"id":[{"id":"10.13039\/501100001807","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001807","name":"Funda\u00e7\u00e3o de Amparo a Pesquisa do Estado de S\u00e3o Paulo","doi-asserted-by":"publisher","award":["AUXPE 0339\/2021"],"award-info":[{"award-number":["AUXPE 0339\/2021"]}],"id":[{"id":"10.13039\/501100001807","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002322","name":"Coordena\u00e7\u00e3o de Aperfei\u00e7oamento de Pessoal de N\u00edvel Superior\u2014Brasil (CAPES)","doi-asserted-by":"publisher","award":["2017-22574-0"],"award-info":[{"award-number":["2017-22574-0"]}],"id":[{"id":"10.13039\/501100002322","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002322","name":"Coordena\u00e7\u00e3o de Aperfei\u00e7oamento de Pessoal de N\u00edvel Superior\u2014Brasil (CAPES)","doi-asserted-by":"publisher","award":["001"],"award-info":[{"award-number":["001"]}],"id":[{"id":"10.13039\/501100002322","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002322","name":"Coordena\u00e7\u00e3o de Aperfei\u00e7oamento de Pessoal de N\u00edvel Superior\u2014Brasil (CAPES)","doi-asserted-by":"publisher","award":["AUXPE 0339\/2021"],"award-info":[{"award-number":["AUXPE 0339\/2021"]}],"id":[{"id":"10.13039\/501100002322","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>MELAS syndrome, characterized by mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes, represents a devastating mitochondrial disease, with the stroke-like episodes being its primary manifestation. Arginine supplementation has been used and recommended as a treatment for these acute attacks; however, insufficient evidence exists to support this treatment for MELAS. The mechanisms underlying the effect of arginine on MELAS pathophysiology remain unclear, although it is hypothesized that arginine could increase nitric oxide availability and, consequently, enhance blood supply to the brain. A more comprehensive understanding of these mechanisms is necessary to improve treatment strategies, such as dose and regimen adjustments; identify which patients could benefit the most; and establish potential markers for follow-up. This review aims to analyze the existing evidence concerning the mechanisms through which arginine supplementation impacts MELAS pathophysiology and provide the current scenario and perspectives for future investigations.<\/jats:p>","DOI":"10.3390\/ijms25073629","type":"journal-article","created":{"date-parts":[[2024,3,25]],"date-time":"2024-03-25T12:47:11Z","timestamp":1711370831000},"page":"3629","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":15,"title":["Arginine Supplementation in MELAS Syndrome: What Do We Know about the Mechanisms?"],"prefix":"10.3390","volume":"25","author":[{"given":"Camila D. S.","family":"Barros","sequence":"first","affiliation":[{"name":"Division of Neurology, Department of Neurology and Neurosurgery, Escola Paulista de Medicina, Universidade Federal de S\u00e3o Paulo, S\u00e3o Paulo 04039-032, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aryane","family":"Coutinho","sequence":"additional","affiliation":[{"name":"Division of Neurology, Department of Neurology and Neurosurgery, Escola Paulista de Medicina, Universidade Federal de S\u00e3o Paulo, S\u00e3o Paulo 04039-032, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Celia H.","family":"Tengan","sequence":"additional","affiliation":[{"name":"Division of Neurology, Department of Neurology and Neurosurgery, Escola Paulista de Medicina, Universidade Federal de S\u00e3o Paulo, S\u00e3o Paulo 04039-032, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,3,24]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"481","DOI":"10.1002\/ana.410160409","article-title":"Mitochondrial myopathy, encephalopathy, lactic acidosis, and strokelike episodes: A distinctive clinical syndrome","volume":"16","author":"Pavlakis","year":"1984","journal-title":"Ann. Neurol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"133","DOI":"10.1196\/annals.1444.011","article-title":"Mitochondrial encephalopathy, lactic acidosis, and strokelike episodes: Basic concepts, clinical phenotype, and therapeutic management of MELAS syndrome","volume":"1142","author":"Sproule","year":"2008","journal-title":"Ann. N. Y. Acad. Sci."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"97","DOI":"10.1016\/j.diabet.2009.11.002","article-title":"Genetic bases of mitochondrial respiratory chain disorders","volume":"36","author":"Rotig","year":"2010","journal-title":"Diabetes Metab."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"104","DOI":"10.1111\/j.1749-6632.2010.05624.x","article-title":"MELAS and L-arginine therapy: Pathophysiology of stroke-like episodes","volume":"1201","author":"Koga","year":"2010","journal-title":"Ann. N. Y. Acad. Sci."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"545","DOI":"10.1212\/WNL.42.3.545","article-title":"Mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS): A correlative study of the clinical features and mitochondrial DNA mutation","volume":"42","author":"Goto","year":"1992","journal-title":"Neurology"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1019","DOI":"10.1016\/j.bbadis.2012.01.010","article-title":"Metabolically induced heteroplasmy shifting and l-arginine treatment reduce the energetic defect in a neuronal-like model of MELAS","volume":"1822","author":"Gueguen","year":"2012","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"615","DOI":"10.1016\/j.bbagen.2011.04.018","article-title":"In vivo functional brain imaging and a therapeutic trial of L-arginine in MELAS patients","volume":"1820","author":"Yoneda","year":"2012","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"816","DOI":"10.1212\/WNL.59.6.816","article-title":"Neuronal hyperexcitability in stroke-like episodes of MELAS syndrome","volume":"59","author":"Iizuka","year":"2002","journal-title":"Neurology"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"61","DOI":"10.2217\/fnl.09.71","article-title":"Pathophysiology of stroke-like episodes in MELAS: Neuron\u2013astrocyte uncoupling in neuronal hyperexcitability","volume":"5","author":"Iizuka","year":"2010","journal-title":"Future Neurol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"827","DOI":"10.1212\/WNL.58.5.827","article-title":"Effects of L-arginine on the acute phase of strokes in three patients with MELAS","volume":"58","author":"Koga","year":"2002","journal-title":"Neurology"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1766","DOI":"10.1212\/01.wnl.0000220197.36849.1e","article-title":"Endothelial dysfunction in MELAS improved by l-arginine supplementation","volume":"66","author":"Koga","year":"2006","journal-title":"Neurology"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"247","DOI":"10.1016\/j.ymgme.2012.06.018","article-title":"Citrulline and arginine utility in treating nitric oxide deficiency in mitochondrial disorders","volume":"107","author":"Emrick","year":"2012","journal-title":"Mol. Genet. Metab."},{"key":"ref_13","first-page":"691","article-title":"Effects of N-acetylcysteine and L-arginine in the antioxidant system of C2C12 cells","volume":"55","author":"Lambertucci","year":"2015","journal-title":"J. Sports Med. Phys. Fitness"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"710","DOI":"10.1212\/01.WNL.0000151976.60624.01","article-title":"L-arginine improves the symptoms of strokelike episodes in MELAS","volume":"64","author":"Koga","year":"2005","journal-title":"Neurology"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"301","DOI":"10.1016\/j.ymgme.2018.01.010","article-title":"8-year retrospective analysis of intravenous arginine therapy for acute metabolic strokes in pediatric mitochondrial disease","volume":"123","author":"Ganetzky","year":"2018","journal-title":"Mol. Genet. Metab."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"e2318","DOI":"10.1212\/WNL.0000000000200299","article-title":"l-Arginine in Mitochondrial Encephalopathy, Lactic Acidosis, and Stroke-like Episodes: A Systematic Review","volume":"98","author":"Stefanetti","year":"2022","journal-title":"Neurology"},{"key":"ref_17","first-page":"1380","article-title":"Patient care standards for primary mitochondrial disease: A consensus statement from the Mitochondrial Medicine Society","volume":"19","author":"Parikh","year":"2017","journal-title":"Genet. Med."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"707","DOI":"10.1097\/MOP.0000000000000954","article-title":"Mitochondrial medicine therapies: Rationale, evidence, and dosing guidelines","volume":"32","author":"Barcelos","year":"2020","journal-title":"Curr. Opin. Pediatr."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"30S","DOI":"10.1177\/0884533617691250","article-title":"Acquired Amino Acid Deficiencies: A Focus on Arginine and Glutamine","volume":"32","author":"Morris","year":"2017","journal-title":"Nutr. Clin. Pract."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"682780","DOI":"10.3389\/fnmol.2021.682780","article-title":"Nitric Oxide Deficiency in Mitochondrial Disorders: The Utility of Arginine and Citrulline","volume":"14","author":"Almannai","year":"2021","journal-title":"Front. Mol. Neurosci."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"532","DOI":"10.3389\/fimmu.2014.00532","article-title":"Metabolism via Arginase or Nitric Oxide Synthase: Two Competing Arginine Pathways in Macrophages","volume":"5","author":"Rath","year":"2014","journal-title":"Front. Immunol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"H651","DOI":"10.1152\/ajpheart.00755.2012","article-title":"Insights into the arginine paradox: Evidence against the importance of subcellular location of arginase and eNOS","volume":"305","author":"Elms","year":"2013","journal-title":"Am. J. Physiol. Heart Circ. Physiol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"2271","DOI":"10.1007\/s00726-014-1825-9","article-title":"L-Arginine and its metabolites in kidney and cardiovascular disease","volume":"46","author":"Popolo","year":"2014","journal-title":"Amino Acids"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"489","DOI":"10.1016\/j.clnu.2008.05.007","article-title":"New indications and controversies in arginine therapy","volume":"27","author":"Coman","year":"2008","journal-title":"Clin. Nutr."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"190","DOI":"10.1016\/j.tips.2005.02.005","article-title":"Mitochondrial nitric oxide synthase","volume":"26","author":"Ghafourifar","year":"2005","journal-title":"Trends Pharmacol. Sci."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1251","DOI":"10.3945\/jn.117.248435","article-title":"Assessment of Nitric Oxide Production in Mitochondrial Encephalomyopathy, Lactic Acidosis, and Stroke-Like Episodes Syndrome with the Use of a Stable Isotope Tracer Infusion Technique","volume":"147","author":"Jahoor","year":"2017","journal-title":"J. Nutr."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"757","DOI":"10.1038\/sj.cdd.4401244","article-title":"Nitric oxide signaling regulates mitochondrial number and function","volume":"10","author":"Lipton","year":"2003","journal-title":"Cell Death Differ."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"17160","DOI":"10.3390\/ijms131217160","article-title":"Nitric oxide in skeletal muscle: Role on mitochondrial biogenesis and function","volume":"13","author":"Tengan","year":"2012","journal-title":"Int. J. Mol. Sci."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"8","DOI":"10.1016\/j.abb.2016.08.010","article-title":"Mitochondrial nitric oxide production supported by reverse electron transfer","volume":"607","author":"Bombicino","year":"2016","journal-title":"Arch. Biochem. Biophys."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1016\/B978-0-12-800254-4.00003-9","article-title":"Heart mitochondrial nitric oxide synthase: A strategic enzyme in the regulation of cellular bioenergetics","volume":"96","author":"Zaobornyj","year":"2014","journal-title":"Vitam. Horm."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"283","DOI":"10.1016\/j.cardiores.2007.03.022","article-title":"Nitric oxide and mitochondrial respiration in the heart","volume":"75","author":"Brown","year":"2007","journal-title":"Cardiovasc. Res."},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Rodan, L.H., Wells, G.D., Banks, L., Thompson, S., Schneiderman, J.E., and Tein, I. (2015). L-Arginine Affects Aerobic Capacity and Muscle Metabolism in MELAS (Mitochondrial Encephalomyopathy, Lactic Acidosis and Stroke-Like Episodes) Syndrome. PLoS ONE, 10.","DOI":"10.1371\/journal.pone.0127066"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"607","DOI":"10.1016\/j.ymgme.2012.01.016","article-title":"Restoration of impaired nitric oxide production in MELAS syndrome with citrulline and arginine supplementation","volume":"105","author":"Hsu","year":"2012","journal-title":"Mol. Genet. Metab."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"407","DOI":"10.1016\/j.ymgme.2016.01.010","article-title":"Impaired nitric oxide production in children with MELAS syndrome and the effect of arginine and citrulline supplementation","volume":"117","author":"Emrick","year":"2016","journal-title":"Mol. Genet. Metab."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"187","DOI":"10.1016\/j.jns.2004.11.026","article-title":"Hypocitrullinemia in patients with MELAS: An insight into the \u201cMELAS paradox\u201d","volume":"229\u2013230","author":"Naini","year":"2005","journal-title":"J. Neurol. Sci."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"2861","DOI":"10.1007\/s00415-018-9057-7","article-title":"Therapeutic regimen of L-arginine for MELAS: 9-year, prospective, multicenter, clinical research","volume":"265","author":"Koga","year":"2018","journal-title":"J. Neurol."},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Rodan, L.H., Poublanc, J., Fisher, J.A., Sobczyk, O., Mikulis, D.J., and Tein, I. (2020). L-arginine effects on cerebrovascular reactivity, perfusion and neurovascular coupling in MELAS (mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes) syndrome. PLoS ONE, 15.","DOI":"10.1371\/journal.pone.0238224"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"534","DOI":"10.1016\/j.jnutbio.2004.03.005","article-title":"Biochemical responses of healthy subjects during dietary supplementation with L-arginine","volume":"15","author":"Evans","year":"2004","journal-title":"J. Nutr. Biochem."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"66","DOI":"10.1016\/j.mito.2015.03.002","article-title":"Cerebral hyperperfusion and decreased cerebrovascular reactivity correlate with neurologic disease severity in MELAS","volume":"22","author":"Rodan","year":"2015","journal-title":"Mitochondrion"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"133","DOI":"10.1016\/j.mito.2006.11.006","article-title":"MELAS and L-arginine therapy","volume":"7","author":"Koga","year":"2007","journal-title":"Mitochondrion"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"852","DOI":"10.1016\/j.neurol.2011.02.038","article-title":"Effect of long-term oral treatment with L-arginine and idebenone on the prevention of stroke-like episodes in an adult MELAS patient","volume":"167","author":"Lekoubou","year":"2011","journal-title":"Rev. Neurol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"479","DOI":"10.1016\/j.ijcard.2016.08.211","article-title":"Unaltered l-arginine\/NO pathway in a MELAS patient: Is mitochondrial NO synthase involved in the MELAS syndrome?","volume":"223","author":"Hanff","year":"2016","journal-title":"Int. J. Cardiol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"196","DOI":"10.1039\/D1MO00416F","article-title":"Integrated proteomic and metabolomic analyses of the mitochondrial neurodegenerative disease MELAS","volume":"18","author":"Li","year":"2022","journal-title":"Mol. Omics"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"191","DOI":"10.1042\/BJ20050272","article-title":"Effects of nitric oxide donors on cybrids harbouring the mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes (MELAS) A3243G mitochondrial DNA mutation","volume":"391","author":"Sandhu","year":"2005","journal-title":"Biochem. J."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"394","DOI":"10.3390\/ijms14010394","article-title":"Nitric oxide synthesis is increased in cybrid cells with m.3243A>G mutation","volume":"14","author":"Gamba","year":"2012","journal-title":"Int. J. Mol. Sci."},{"key":"ref_46","doi-asserted-by":"crossref","unstructured":"Barros, C.D.S., Livramento, J.B., Mouro, M.G., Higa, E.M.S., Moraes, C.T., and Tengan, C.H. (2021). L-Arginine Reduces Nitro-Oxidative Stress in Cultured Cells with Mitochondrial Deficiency. Nutrients, 13.","DOI":"10.3390\/nu13020534"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"771","DOI":"10.1016\/j.bbrc.2007.05.184","article-title":"The role of nitric oxide in muscle fibers with oxidative phosphorylation defects","volume":"359","author":"Tengan","year":"2007","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"20780","DOI":"10.1038\/srep20780","article-title":"Integrated analysis of the involvement of nitric oxide synthesis in mitochondrial proliferation, mitochondrial deficiency and apoptosis in skeletal muscle fibres","volume":"6","author":"Rodrigues","year":"2016","journal-title":"Sci. Rep."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"1873","DOI":"10.1161\/01.STR.25.9.1873","article-title":"Cerebral hyperemia in MELAS","volume":"25","author":"Gropen","year":"1994","journal-title":"Stroke"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"810","DOI":"10.1179\/016164101101199397","article-title":"Serial MRI findings in patient with chronic cryptococcus meningo-encephalitis","volume":"23","author":"Narai","year":"2001","journal-title":"Neurol. Res."},{"key":"ref_51","doi-asserted-by":"crossref","unstructured":"Ikawa, M., Okazawa, H., Nakamoto, Y., and Yoneda, M. (2020). PET Imaging for Oxidative Stress in Neurodegenerative Disorders Associated with Mitochondrial Dysfunction. Antioxidants, 9.","DOI":"10.3390\/antiox9090861"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"325","DOI":"10.1111\/j.1552-6569.2001.tb00057.x","article-title":"Discordance between cerebral oxygen and glucose metabolism, and hemodynamics in a mitochondrial encephalomyopathy, lactic acidosis, and strokelike episode patient","volume":"11","author":"Nariai","year":"2001","journal-title":"J. Neuroimaging"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"276","DOI":"10.1016\/j.mito.2021.06.012","article-title":"Metabolic abnormality in acute stroke-like lesion and its relationship with focal cerebral blood flow in patients with MELAS: Evidence from proton MR spectroscopy and arterial spin labeling","volume":"59","author":"Wang","year":"2021","journal-title":"Mitochondrion"},{"key":"ref_54","doi-asserted-by":"crossref","unstructured":"Wang, R., Liu, X., Sun, C., Hu, B., Yang, L., Liu, Y., Geng, D., Lin, J., and Li, Y. (2023). Altered Neurovascular Coupling in Patients with Mitochondrial Myopathy, Encephalopathy, Lactic Acidosis, and Stroke-Like Episodes (MELAS): A Combined Resting-State fMRI and Arterial Spin Labeling Study. J. Magn. Reson. Imaging.","DOI":"10.1002\/jmri.29035"},{"key":"ref_55","doi-asserted-by":"crossref","unstructured":"Stackhouse, T.L., and Mishra, A. (2021). Neurovascular Coupling in Development and Disease: Focus on Astrocytes. Front. Cell Dev. Biol., 9.","DOI":"10.3389\/fcell.2021.702832"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"647","DOI":"10.1177\/0271678X15617954","article-title":"Neurovascular coupling in humans: Physiology, methodological advances and clinical implications","volume":"36","author":"Phillips","year":"2016","journal-title":"J. Cereb. Blood Flow. Metab."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"2178","DOI":"10.1161\/STROKEAHA.123.042705","article-title":"The Ever-Evolving Concept of the Neurovascular Unit","volume":"54","author":"Alkayed","year":"2023","journal-title":"Stroke"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"597","DOI":"10.1038\/s41582-022-00703-z","article-title":"The neurovascular unit and systemic biology in stroke\u2014Implications for translation and treatment","volume":"18","author":"Tiedt","year":"2022","journal-title":"Nat. Rev. Neurol."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"1162757","DOI":"10.3389\/fnetp.2023.1162757","article-title":"Two decades of astrocytes in neurovascular coupling","volume":"3","author":"Lia","year":"2023","journal-title":"Front. Netw. Physiol."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"749026","DOI":"10.3389\/fnagi.2021.749026","article-title":"From Neurodevelopmental to Neurodegenerative Disorders: The Vascular Continuum","volume":"13","author":"Ouellette","year":"2021","journal-title":"Front. Aging Neurosci."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"436","DOI":"10.1016\/j.neuroimage.2012.10.052","article-title":"Measuring relative timings of brain activities using fMRI","volume":"66","author":"Katwal","year":"2013","journal-title":"Neuroimage"},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"384","DOI":"10.4329\/wjr.v2.i10.384","article-title":"Arterial spin labeling in neuroimaging","volume":"2","author":"Petcharunpaisan","year":"2010","journal-title":"World J. Radiol."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"729201","DOI":"10.3389\/fphys.2021.729201","article-title":"Nitric Oxide Pathways in Neurovascular Coupling Under Normal and Stress Conditions in the Brain: Strategies to Rescue Aberrant Coupling and Improve Cerebral Blood Flow","volume":"12","author":"Lourenco","year":"2021","journal-title":"Front. Physiol."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"2702","DOI":"10.1253\/circj.CJ-10-0044","article-title":"Abnormal myocardial energy-production state in mitochondrial cardiomyopathy and acute response to L-arginine infusion. C-11 acetate kinetics revealed by positron emission tomography","volume":"74","author":"Arakawa","year":"2010","journal-title":"Circ. J."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"1602S","DOI":"10.1093\/jn\/137.6.1602S","article-title":"Arginine metabolism: Boundaries of our knowledge","volume":"137","author":"Morris","year":"2007","journal-title":"J. Nutr."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"2465","DOI":"10.1172\/JCI82925","article-title":"Increased mitochondrial arginine metabolism supports bioenergetics in asthma","volume":"126","author":"Xu","year":"2016","journal-title":"J. Clin. Investig."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"173","DOI":"10.1016\/B978-0-12-821751-1.00016-6","article-title":"Neuroimaging in mitochondrial disease","volume":"194","author":"Distelmaier","year":"2023","journal-title":"Handb. Clin. Neurol."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"608","DOI":"10.1016\/j.bbagen.2011.09.005","article-title":"Molecular pathology of MELAS and L-arginine effects","volume":"1820","author":"Koga","year":"2012","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"481","DOI":"10.1016\/j.braindev.2004.01.006","article-title":"Beneficial effect of L-arginine for stroke-like episode in MELAS","volume":"26","author":"Kubota","year":"2004","journal-title":"Brain Dev."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"82","DOI":"10.1111\/ane.13027","article-title":"MELAS: Monitoring treatment with magnetic resonance spectroscopy","volume":"139","author":"Hovsepian","year":"2019","journal-title":"Acta Neurol. Scand."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"10","DOI":"10.1016\/j.freeradbiomed.2015.05.039","article-title":"Oxidative stress in inherited mitochondrial diseases","volume":"88 Pt A","author":"Hayashi","year":"2015","journal-title":"Free Radic. Biol. Med."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"306","DOI":"10.1016\/j.mito.2009.04.002","article-title":"Accumulation of oxidative stress around the stroke-like lesions of MELAS patients","volume":"9","author":"Katayama","year":"2009","journal-title":"Mitochondrion"},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"S45","DOI":"10.1016\/S0168-8227(01)00335-7","article-title":"Enhanced oxidative damage in human cells harboring A3243G mutation of mitochondrial DNA: Implication of oxidative stress in the pathogenesis of mitochondrial diabetes","volume":"54","author":"Pang","year":"2001","journal-title":"Diabetes Res. Clin. Pract."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"235","DOI":"10.1016\/j.freeradbiomed.2018.08.020","article-title":"Different mitochondrial genetic defects exhibit the same protein signature of metabolism in skeletal muscle of PEO and MELAS patients: A role for oxidative stress","volume":"126","author":"Santacatterina","year":"2018","journal-title":"Free Radic. Biol. Med."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"M110.002964","DOI":"10.1074\/mcp.M110.002964","article-title":"Increased protein nitration in mitochondrial diseases: Evidence for vessel wall involvement","volume":"10","author":"Vattemi","year":"2011","journal-title":"Mol. Cell Proteom."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"144","DOI":"10.1016\/j.mito.2009.01.011","article-title":"PET imaging of redox and energy states in stroke-like episodes of MELAS","volume":"9","author":"Ikawa","year":"2009","journal-title":"Mitochondrion"},{"key":"ref_77","first-page":"1665","article-title":"Oral L-arginine supplementation in patients with mild arterial hypertension and its effect on plasma level of asymmetric dimethylarginine, L-citruline, L-arginine and antioxidant status","volume":"16","author":"Jabecka","year":"2012","journal-title":"Eur. Rev. Med. Pharmacol. Sci."},{"key":"ref_78","first-page":"449","article-title":"Effects of L- Arginine Supplementation on Antioxidant Status and Body Composition in Obese Patients with Pre-diabetes: A Randomized Controlled Clinical Trial","volume":"4","author":"Fazelian","year":"2014","journal-title":"Adv. Pharm. Bull."},{"key":"ref_79","first-page":"342","article-title":"The effect of oral L-arginine supplementation on fasting glucose, HbA1c, nitric oxide and total antioxidant status in diabetic patients with atherosclerotic peripheral arterial disease of lower extremities","volume":"16","author":"Jablecka","year":"2012","journal-title":"Eur. Rev. Med. Pharmacol. Sci."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/25\/7\/3629\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T14:17:51Z","timestamp":1760105871000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/25\/7\/3629"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,3,24]]},"references-count":79,"journal-issue":{"issue":"7","published-online":{"date-parts":[[2024,4]]}},"alternative-id":["ijms25073629"],"URL":"https:\/\/doi.org\/10.3390\/ijms25073629","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,3,24]]}}}