{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,8]],"date-time":"2026-10-08T19:12:13Z","timestamp":1791486733448,"version":"4.3.4"},"reference-count":79,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2025,8,21]],"date-time":"2025-08-21T00:00:00Z","timestamp":1755734400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Life"],"abstract":"<jats:p>The renin-angiotensin system (RAS) has evolved from being considered solely a peripheral endocrine system for cardiovascular control to being recognized as a complex molecular network with important functions in the central nervous system (CNS) and peripheral nervous system (PNS). Here we examine the organization, mechanisms of action, and clinical implications of cerebral RAS in physiological conditions and in various neurological pathologies. The cerebral RAS operates autonomously, synthesizing its main components locally due to restrictions imposed by the blood\u2013brain barrier. The key elements of the system are (pro)renin; (pro)renin receptor (PRR); angiotensinogen; angiotensin-converting enzyme types 1 and 2 (ACE1 and ACE2); angiotensin I (AngI), angiotensin II (AngII), angiotensin III (AngIII), angiotensin IV (AngIV), angiotensin A (AngA), and angiotensin 1-7 (Ang(1-7)) peptides; RAS-regulating aminopeptidases; and AT1 (AT1R), AT2 (AT2R), AT4 (AT4R\/IRAP), and Mas (MasR) receptors. More recently, alamandine and its MrgD receptor have been included. They are distributed in specific brain regions such as the hypothalamus, hippocampus, cerebral cortex, and brainstem. The system is organized into two opposing axes: the classical axis (renin\/ACE1\/AngII\/AT1R) with vasoconstrictive, proinflammatory, and prooxidative effects, and the alternative axes AngII\/AT2R, AngIV\/AT4R\/IRAP, ACE2\/Ang(1-7)\/MasR and alamandine\/MrgD receptor, with vasodilatory, anti-inflammatory, and neuroprotective properties. This functional duality allows us to understand its role in neurological physiopathology. RAS dysregulation is implicated in multiple neurodegenerative diseases, including Alzheimer\u2019s disease (AD), Parkinson\u2019s disease (PD), and neuropsychiatric disorders such as depression and anxiety. In brain aging, an imbalance toward hyperactivation of the renin\/ACE1\/AngII\/AT1R axis is observed, contributing to cognitive impairment and neuroinflammation. Epidemiological studies and clinical trials have shown that pharmacological modulation of the RAS using ACE inhibitors (ACEIs) and AT1R antagonists (ARA-II) not only controls blood pressure but also offers neuroprotective benefits, reducing the incidence of cognitive decline and dementia. These effects are attributed to direct mechanisms on the CNS, including reduction of oxidative stress, decreased neuroinflammation, and improved cerebral blood flow.<\/jats:p>","DOI":"10.3390\/life15081333","type":"journal-article","created":{"date-parts":[[2025,8,22]],"date-time":"2025-08-22T07:41:45Z","timestamp":1755848505000},"page":"1333","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":15,"title":["Physiopathology of the Brain Renin-Angiotensin System"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6149-090X","authenticated-orcid":false,"given":"Cristina","family":"Cueto-Ure\u00f1a","sequence":"first","affiliation":[{"name":"Experimental and Clinical Physiopathology Research Group CTS-1039, Department of Health Sciences, School of Health Sciences, University of Ja\u00e9n, E-23071 Ja\u00e9n, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9379-203X","authenticated-orcid":false,"given":"Mar\u00eda Jes\u00fas","family":"Ram\u00edrez-Exp\u00f3sito","sequence":"additional","affiliation":[{"name":"Experimental and Clinical Physiopathology Research Group CTS-1039, Department of Health Sciences, School of Health Sciences, University of Ja\u00e9n, E-23071 Ja\u00e9n, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6575-8240","authenticated-orcid":false,"given":"Mar\u00eda Pilar","family":"Carrera-Gonz\u00e1lez","sequence":"additional","affiliation":[{"name":"Experimental and Clinical Physiopathology Research Group CTS-1039, Department of Health Sciences, School of Health Sciences, University of Ja\u00e9n, E-23071 Ja\u00e9n, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2950-5614","authenticated-orcid":false,"given":"Jos\u00e9 Manuel","family":"Mart\u00ednez-Martos","sequence":"additional","affiliation":[{"name":"Experimental and Clinical Physiopathology Research Group CTS-1039, Department of Health Sciences, School of Health Sciences, University of Ja\u00e9n, E-23071 Ja\u00e9n, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,8,21]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"905","DOI":"10.1016\/j.sjbs.2020.01.026","article-title":"Role of brain renin angiotensin system in neurodegeneration: An update","volume":"27","author":"Abiodun","year":"2020","journal-title":"Saudi J. Biol. Sci."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"8883492","DOI":"10.1155\/2023\/8883492","article-title":"Brain Renin-Angiotensin System: From Physiology to Pathology in Neuronal Complications Induced by SARS-CoV-2","volume":"2023","author":"Ahmadi","year":"2023","journal-title":"Anal. Cell Pathol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"22","DOI":"10.1186\/s40035-024-00410-3","article-title":"The role of the brain renin-angiotensin system in Parkinson s disease","volume":"13","author":"Labandeira","year":"2024","journal-title":"Transl. Neurodegener."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"e18495","DOI":"10.1111\/jcmm.18495","article-title":"The potential role of brain renin-angiotensin system in the neuropathology of Parkinson disease: Friend, foe or turncoat?","volume":"28","author":"Albuhadily","year":"2024","journal-title":"J. Cell Mol. Med."},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Sunanda, T., Ray, B., Mahalakshmi, A.M., Bhat, A., Rashan, L., Rungratanawanich, W., Song, B.J., Essa, M.M., Sakharkar, M.K., and Chidambaram, S.B. (2021). Mitochondria-Endoplasmic Reticulum Crosstalk in Parkinson\u2019s Disease: The Role of Brain Renin Angiotensin System Components. Biomolecules, 11.","DOI":"10.3390\/biom11111669"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"e14525","DOI":"10.1111\/cns.14525","article-title":"Role of brain renin-angiotensin system in depression: A new perspective","volume":"30","author":"Ali","year":"2024","journal-title":"CNS Neurosci. Ther."},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Kilic, A., Ipek, B.E., Tatonyan, S., Kilic, K., Demirci, H., Atalar, F., Ustunova, S., and Dariyerli, N. (2025). Alamandine enhanced spatial memory in rats by reducing neuroinflammation and altering BDNF levels in the hippocampus and prefrontal cortex. Sci. Rep., 15.","DOI":"10.1038\/s41598-025-95683-7"},{"key":"ref_8","first-page":"1065","article-title":"Extrarenal angiotensin-forming enzymes","volume":"5","author":"Genest","year":"1983","journal-title":"Clin. Exp. Hypertens. A"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1159\/000186026","article-title":"ACE inhibitors and the kidney","volume":"55","author":"Johnston","year":"1990","journal-title":"Nephron"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"973","DOI":"10.1038\/labinvest.3780100","article-title":"Regulation of aminopeptidase A in human brain tumor vasculature: Evidence for a role of transforming growth factor-beta","volume":"80","author":"Lohm","year":"2000","journal-title":"Lab. Investig."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"161","DOI":"10.1055\/s-2007-978614","article-title":"Comparative distribution of glutamyl and aspartyl aminopeptidase activities in mouse organs","volume":"32","author":"Martinez","year":"2000","journal-title":"Horm. Metab. Res. = Hormon- und Stoffwechselforschung = Horm. Et Metab."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"24543","DOI":"10.1016\/S0021-9258(19)74499-8","article-title":"Molecular cloning of a novel angiotensin II receptor isoform involved in phosphotyrosine phosphatase inhibition","volume":"268","author":"Kambayashi","year":"1993","journal-title":"J. Biol. Chem."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"24539","DOI":"10.1016\/S0021-9258(19)74498-6","article-title":"Expression cloning of type 2 angiotensin II receptor reveals a unique class of seven-transmembrane receptors","volume":"268","author":"Mukoyama","year":"1993","journal-title":"J. Biol. Chem."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1473","DOI":"10.3233\/JAD-215051","article-title":"Renin-Angiotensin System Alterations in the Human Alzheimer\u2019s Disease Brain","volume":"84","author":"Ismael","year":"2021","journal-title":"J. Alzheimers Dis."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"101612","DOI":"10.1016\/j.arr.2022.101612","article-title":"Targeting brain Renin-Angiotensin System for the prevention and treatment of Alzheimer\u2019s disease: Past, present and future","volume":"77","author":"Gouveia","year":"2022","journal-title":"Ageing Res. Rev."},{"key":"ref_16","first-page":"1900","article-title":"New Approaches Targeting the Renin-Angiotensin System: Inhibition of Brain Aminopeptidase A, ACE2 Ubiquitination, and Angiotensinogen","volume":"39","author":"Lazartigues","year":"2023","journal-title":"Can. J. Cardiol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"6","DOI":"10.1161\/HYPERTENSIONAHA.119.12675","article-title":"Evolution of a New Class of Antihypertensive Drugs: Targeting the Brain Renin-Angiotensin System","volume":"75","author":"Touyz","year":"2020","journal-title":"Hypertension"},{"key":"ref_18","first-page":"125","article-title":"[The renin-angiotensin system and the brain]","volume":"38","author":"Vergara","year":"2021","journal-title":"Hipertens. Riesgo Vasc."},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Loera-Valencia, R., Eroli, F., Garcia-Ptacek, S., and Maioli, S. (2021). Brain Renin-Angiotensin System as Novel and Potential Therapeutic Target for Alzheimer\u2019s Disease. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms221810139"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1727","DOI":"10.1042\/CS20210579","article-title":"Fifty years of research on the brain renin-angiotensin system: What have we learned?","volume":"135","author":"Uijl","year":"2021","journal-title":"Clin. Sci."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"115192","DOI":"10.1016\/j.intimp.2025.115192","article-title":"Role of the renin-angiotensin-aldosterone system in sepsis and its therapeutic targets","volume":"162","author":"Chen","year":"2025","journal-title":"Int. Immunopharmacol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"102423","DOI":"10.1016\/j.jchemneu.2024.102423","article-title":"Impacts of SARS-CoV-2 on brain renin angiotensin system related signaling and its subsequent complications on brain: A theoretical perspective","volume":"138","author":"Etebar","year":"2024","journal-title":"J. Chem. Neuroanat."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"100424","DOI":"10.1016\/j.mcpro.2022.100424","article-title":"Soluble ANPEP Released From Human Astrocytes as a Positive Regulator of Microglial Activation and Neuroinflammation: Brain Renin-Angiotensin System in Astrocyte-Microglia Crosstalk","volume":"21","author":"Kim","year":"2022","journal-title":"Mol. Cell Proteom."},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Martinez-Martos, J.M., Canton-Habas, V., Rich-Ruiz, M., Reyes-Medina, M.J., Ramirez-Exposito, M.J., and Carrera-Gonzalez, M.D.P. (2024). Sexual and Metabolic Differences in Hippocampal Evolution: Alzheimer\u2019s Disease Implications. Life, 14.","DOI":"10.3390\/life14121547"},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Gouveia, F., Perez, M.C., Bicker, J., Silva, A., Santos, A.E., Pereira, C.F., Camins, A., Falcao, A., Cruz, T., and Ettcheto, M. (2025). Protective effects of irbesartan against neurodegeneration in APP\/PS1 mice: Unraveling its triple anti-apoptotic, anti-inflammatory and anti-oxidant action. Biomed. Pharmacother., 188.","DOI":"10.1016\/j.biopha.2025.118167"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"469","DOI":"10.3233\/JAD-181035","article-title":"Contributions by the Brain Renin-Angiotensin System to Memory, Cognition, and Alzheimer\u2019s Disease","volume":"67","author":"Wright","year":"2019","journal-title":"J. Alzheimers Dis."},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Cosarderelioglu, C., Nidadavolu, L.S., George, C.J., Oh, E.S., Bennett, D.A., Walston, J.D., and Abadir, P.M. (2020). Brain Renin-Angiotensin System at the Intersect of Physical and Cognitive Frailty. Front. Neurosci., 14.","DOI":"10.3389\/fnins.2020.586314"},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Hanuska, A., Ribiczey, P., Kato, E., Papp, Z.T., Varga, Z.V., Giricz, Z., Toth, Z.E., Konczol, K., Zsembery, A., and Zelles, T. (2024). Potentiation of NMDA Receptors by AT1 Angiotensin Receptor Activation in Layer V Pyramidal Neurons of the Rat Prefrontal Cortex. Int. J. Mol. Sci., 25.","DOI":"10.3390\/ijms252312644"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"195","DOI":"10.13004\/kjnt.2023.19.e26","article-title":"Mini-Review: Role of Drugs Affecting Renin-Angiotensin System (RAS) in Traumatic Brain Injury (TBI): What We Know and What We Should Know","volume":"19","author":"Sarpolaki","year":"2023","journal-title":"Korean J. Neurotrauma"},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Barak, R., Goshtasbi, G., Fatehi, R., and Firouzabadi, N. (2024). Signaling pathways and genetics of brain Renin angiotensin system in psychiatric disorders: State of the art. Pharmacol. Biochem. Behav., 236.","DOI":"10.1016\/j.pbb.2023.173706"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"575","DOI":"10.1210\/jcem-32-4-575","article-title":"The effect of the heptapeptide (2-8) and hexapeptide (3-8) fragments of angiotensin II on aldosterone secretion","volume":"32","author":"Coghlan","year":"1971","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"E1","DOI":"10.1161\/01.RES.87.5.e1","article-title":"A novel angiotensin-converting enzyme-related carboxypeptidase (ACE2) converts angiotensin I to angiotensin 1-9","volume":"87","author":"Donoghue","year":"2000","journal-title":"Circ. Res."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"149739","DOI":"10.1016\/j.brainres.2025.149739","article-title":"ACE2\/Angiotensin-(1-7)\/Mas and the brain","volume":"1863","author":"Haibara","year":"2025","journal-title":"Brain Res."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"865","DOI":"10.1016\/j.jash.2015.08.005","article-title":"Angiotensin-(1-7) enhances the effects of angiotensin II on the cardiac sympathetic afferent reflex and sympathetic activity in rostral ventrolateral medulla in renovascular hypertensive rats","volume":"9","author":"Li","year":"2015","journal-title":"J. Am. Soc. Hypertens."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"84","DOI":"10.1097\/MNH.0b013e3283414d40","article-title":"New insights into angiotensin receptor actions: From blood pressure to aging","volume":"20","author":"Stegbauer","year":"2011","journal-title":"Curr. Opin. Nephrol. Hypertens."},{"key":"ref_36","first-page":"1283","article-title":"Protective effect of angiotensin-(1-7) against hyperglycaemia-induced injury in H9c2 cardiomyoblast cells via the PI3K\/Akt signaling pathway","volume":"41","author":"Yang","year":"2018","journal-title":"Int. J. Mol. Med."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"505","DOI":"10.1152\/physrev.00023.2016","article-title":"The ACE2\/Angiotensin-(1-7)\/MAS Axis of the Renin-Angiotensin System: Focus on Angiotensin-(1-7)","volume":"98","author":"Santos","year":"2018","journal-title":"Physiol. Rev."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"628","DOI":"10.52586\/4972","article-title":"The renin-angiotensin system in central nervous system tumors and degenerative diseases","volume":"26","author":"Haron","year":"2021","journal-title":"Front. Biosci."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1104","DOI":"10.1161\/CIRCRESAHA.113.301077","article-title":"Discovery and characterization of alamandine: A novel component of the renin-angiotensin system","volume":"112","author":"Lautner","year":"2013","journal-title":"Circ. Res."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"104880","DOI":"10.1016\/j.yhbeh.2020.104880","article-title":"Alamandine through MrgD receptor induces antidepressant-like effect in transgenic rats with low brain angiotensinogen","volume":"127","author":"Goncalves","year":"2021","journal-title":"Horm. Behav."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"105551","DOI":"10.1016\/j.yhbeh.2024.105551","article-title":"Anxiolytic effect of alamandine in male transgenic rats with low brain angiotensinogen is dependent on activation of MrgD receptors","volume":"163","author":"Mourao","year":"2024","journal-title":"Horm. Behav."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"27963","DOI":"10.31083\/RCM27963","article-title":"Novel Antihypertensive Medications to Target the Renin-Angiotensin System: Mechanisms and Research","volume":"26","author":"Jiang","year":"2025","journal-title":"Rev. Cardiovasc. Med."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"R513","DOI":"10.1152\/ajpregu.00308.2020","article-title":"Alamandine but not angiotensin-(1-7) produces cardiovascular effects at the rostral insular cortex","volume":"321","author":"Marins","year":"2021","journal-title":"Am. J. Physiol. Regul. Integr. Comp. Physiol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"137568","DOI":"10.1016\/j.neulet.2023.137568","article-title":"Alamandine injection in the periaqueductal gray and rostral ventromedial medulla attenuates allodynia induced by sciatic nerve ligation in rats","volume":"818","author":"Gholami","year":"2024","journal-title":"Neurosci. Lett."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"e08440","DOI":"10.1016\/j.heliyon.2021.e08440","article-title":"Localization and expression of the Mas-related G-protein coupled receptor member D (MrgD) in the mouse brain","volume":"7","author":"Hami","year":"2021","journal-title":"Heliyon"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"3483","DOI":"10.2174\/0929867329666220204145730","article-title":"Alamandine Induces Neuroprotection in Ischemic Stroke Models","volume":"29","author":"Goncalves","year":"2022","journal-title":"Curr. Med. Chem."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"1565","DOI":"10.1007\/s13311-023-01435-8","article-title":"The Renin Angiotensin System as a Therapeutic Target in Traumatic Brain Injury","volume":"20","author":"Villapol","year":"2023","journal-title":"Neurotherapeutics"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"130","DOI":"10.1007\/s00221-025-07072-1","article-title":"Unraveling the role of brain renin angiotensin system in vascular dementia: Mechanisms and therapeutic perspectives","volume":"243","author":"Kumar","year":"2025","journal-title":"Exp. Brain Res."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"109809","DOI":"10.1016\/j.cellsig.2020.109809","article-title":"The counter regulatory axis of the renin angiotensin system in the brain and ischaemic stroke: Insight from preclinical stroke studies and therapeutic potential","volume":"76","author":"McFall","year":"2020","journal-title":"Cell Signal"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"9293553","DOI":"10.1155\/2021\/9293553","article-title":"Recent Advances in the Endogenous Brain Renin-Angiotensin System and Drugs Acting on It","volume":"2021","author":"Urmila","year":"2021","journal-title":"J. Renin Angiotensin Aldosterone Syst."},{"key":"ref_51","doi-asserted-by":"crossref","unstructured":"Lucas, L.C., Kimbark, K.D., Vernail, V.L., Silberman, Y., and Arnold, A.C. (2025). Angiotensin-(1-7) protective effects in neurocognitive disorders: Molecular mechanisms to therapeutic implications. Front. Physiol., 16.","DOI":"10.3389\/fphys.2025.1565270"},{"key":"ref_52","doi-asserted-by":"crossref","unstructured":"Jackson, L., Eldahshan, W., Fagan, S.C., and Ergul, A. (2018). Within the Brain: The Renin Angiotensin System. Int. J. Mol. Sci., 19.","DOI":"10.3390\/ijms19030876"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"3167","DOI":"10.1210\/en.2016-1131","article-title":"Angiotensin Type-2 Receptors Influence the Activity of Vasopressin Neurons in the Paraventricular Nucleus of the Hypothalamus in Male Mice","volume":"157","author":"Pitra","year":"2016","journal-title":"Endocrinology"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"133","DOI":"10.1007\/s00424-012-1102-2","article-title":"The brain renin-angiotensin system: A diversity of functions and implications for CNS diseases","volume":"465","author":"Wright","year":"2013","journal-title":"Pflugers Arch."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"156936","DOI":"10.1016\/j.cyto.2025.156936","article-title":"ADAM17\/ACE2 interaction mediates cadmium-induced brain damage and neuroinflammation in Wistar rats","volume":"190","author":"Morsi","year":"2025","journal-title":"Cytokine"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"1055","DOI":"10.1042\/CS20171549","article-title":"Neuroprotection via AT(2) receptor agonists in ischemic stroke","volume":"132","author":"Bennion","year":"2018","journal-title":"Clin. Sci."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"1079","DOI":"10.1007\/s11011-021-00728-1","article-title":"Manifestation of renin angiotensin system modulation in traumatic brain injury","volume":"36","author":"Mirzahosseini","year":"2021","journal-title":"Metab. Brain Dis."},{"key":"ref_58","doi-asserted-by":"crossref","unstructured":"Oyesiji Abiodun, A., AlDosari, D.I., Alghamdi, A., Aziz Al-Amri, A., Ahmad, S., and Ola, M.S. (2023). Diabetes-induced stimulation of the renin-angiotensin system in the rat brain cortex. Saudi J. Biol. Sci., 30.","DOI":"10.1016\/j.sjbs.2023.103779"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1007\/s00441-012-1354-3","article-title":"Immunohistochemical localization of the angiotensin-(1-7) receptor Mas in the murine forebrain","volume":"348","author":"Freund","year":"2012","journal-title":"Cell Tissue Res."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"1051","DOI":"10.1002\/ana.27204","article-title":"The Use of Antihypertensive Medication and In Vivo Alzheimer\u2019s Disease Pathology","volume":"97","author":"Keum","year":"2025","journal-title":"Ann. Neurol."},{"key":"ref_61","doi-asserted-by":"crossref","unstructured":"Danigo, A., Rovini, A., Bessaguet, F., Bouchenaki, H., Bernard, A., Sturtz, F., Bourthoumieu, S., Desmouliere, A., Magy, L., and Demiot, C. (2021). The Angiotensin II Type 2 Receptor, a Target for Protection and Regeneration of the Peripheral Nervous System?. Pharmaceuticals, 14.","DOI":"10.3390\/ph14030175"},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"C141","DOI":"10.1152\/ajpcell.00533.2022","article-title":"The hypothalamus as a key regulator of glucose homeostasis: Emerging roles of the brain renin-angiotensin system","volume":"325","author":"Pan","year":"2023","journal-title":"Am. J. Physiol. Cell Physiol."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"6371048","DOI":"10.1155\/2022\/6371048","article-title":"Controlled Hemorrhage Sensitizes Angiotensin II-Elicited Hypertension through Activation of the Brain Renin-Angiotensin System Independently of Endoplasmic Reticulum Stress","volume":"2022","author":"Wu","year":"2022","journal-title":"Oxid. Med. Cell Longev."},{"key":"ref_64","doi-asserted-by":"crossref","unstructured":"Chang, Y.S., Lin, C.L., Lee, C.W., Lin, H.C., Wu, Y.T., and Shih, Y.H. (2022). Exercise Normalized the Hippocampal Renin-Angiotensin System and Restored Spatial Memory Function, Neurogenesis, and Blood-Brain Barrier Permeability in the 2K1C-Hypertensive Mouse. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms23105531"},{"key":"ref_65","doi-asserted-by":"crossref","unstructured":"Dzidic-Krivic, A., Fajkic, A., Farhat, E.K., Lekic, L., Ejubovic, A., Vukas, S.K., Ejubovic, M., Lepara, O., and Sher, E.K. (2025). Linking Metabolic Syndrome to Neurodegeneration Mechanisms and Potential Treatments. Mol. Neurobiol.","DOI":"10.1007\/s12035-025-04947-w"},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"104013","DOI":"10.1016\/j.mcn.2025.104013","article-title":"Striatal damage may underlie motor learning impairment following experimental mild traumatic brain injury in mice","volume":"133","author":"Machado","year":"2025","journal-title":"Mol. Cell Neurosci."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"3353","DOI":"10.1007\/s10072-021-05856-1","article-title":"The potential role of renin-angiotensin system in mild traumatic brain injury","volume":"43","author":"Cardoso","year":"2022","journal-title":"Neurol. Sci."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"1025","DOI":"10.4103\/1673-5374.270304","article-title":"The extended renin-angiotensin system: A promising target for traumatic brain injury therapeutics","volume":"15","author":"Janatpour","year":"2020","journal-title":"Neural Regen. Res."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"149266","DOI":"10.1016\/j.brainres.2024.149266","article-title":"Involvement of Renin-Angiotensin system (RAS) components in mild traumatic brain injury","volume":"1846","author":"Machado","year":"2025","journal-title":"Brain Res."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"2112","DOI":"10.1002\/acn3.52132","article-title":"Associations of renin-angiotensin system inhibitor use with brain insulin signaling and neuropathology","volume":"11","author":"Tong","year":"2024","journal-title":"Ann. Clin. Transl. Neurol."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"332","DOI":"10.1186\/s13287-025-04430-2","article-title":"Renin-angiotensin system as an emerging target to modulate adult neurogenesis in health and disease","volume":"16","author":"Parga","year":"2025","journal-title":"Stem Cell Res. Ther."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"149777","DOI":"10.1016\/j.brainres.2025.149777","article-title":"Trophic factors and essential oils as potential neuromodulators of Renin-Angiotensin system","volume":"1863","author":"Crespo","year":"2025","journal-title":"Brain Res."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"644","DOI":"10.1161\/HYPERTENSIONAHA.121.17595","article-title":"Blood-Brain Barrier Crossing Renin-Angiotensin System Drugs: Considerations for Dementia and Cognitive Decline","volume":"78","author":"Glodzik","year":"2021","journal-title":"Hypertension"},{"key":"ref_74","first-page":"841","article-title":"The Renin-Angiotensin System and the Neurodegenerative Diseases: A Brief Review","volume":"24","author":"Kangussu","year":"2017","journal-title":"Protein Pept. Lett."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"26331055231151926","DOI":"10.1177\/26331055231151926","article-title":"SARS-CoV-2 and Hypertension: Evidence Supporting Invasion into the Brain Via Baroreflex Circuitry and the Role of Imbalanced Renin-Angiotensin-Aldosterone-System","volume":"18","author":"Oliveira","year":"2023","journal-title":"Neurosci. Insights"},{"key":"ref_76","doi-asserted-by":"crossref","unstructured":"Rodriguez-Perez, A.I., Serrano-Heras, G., Labandeira, C.M., Camacho-Meno, L., Castro-Robles, B., Suarez-Quintanilla, J.A., Munoz-Lopez, M., Piqueras-Landete, P., Guerra, M.J., and Segura, T. (2025). Serum angiotensin type-1 receptor autoantibodies and neurofilament light chain as markers of neuroaxonal damage in post-COVID patients. Front. Immunol., 16.","DOI":"10.3389\/fimmu.2025.1571027"},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"149640","DOI":"10.1016\/j.brainres.2025.149640","article-title":"Long-term treatment with haloperidol modulates angiotensin I-converting enzyme (ACE) activity in transgenic animal model with construct validity for schizophrenia studies","volume":"1859","author":"Oyadomari","year":"2025","journal-title":"Brain Res."},{"key":"ref_78","doi-asserted-by":"crossref","unstructured":"Gonzalez-Sanchez, M., Ramirez-Exposito, M.J., and Martinez-Martos, J.M. (2025). Pathophysiology, Clinical Heterogeneity, and Therapeutic Advances in Amyotrophic Lateral Sclerosis: A Comprehensive Review of Molecular Mechanisms, Diagnostic Challenges, and Multidisciplinary Management Strategies. Life, 15.","DOI":"10.3390\/life15040647"},{"key":"ref_79","doi-asserted-by":"crossref","unstructured":"Dutra-Tavares, A.C., Maia, J.G., de Souza, T.P., Filgueiras, C.C., Ribeiro-Carvalho, A., Manhaes, A.C., and Abreu-Villaca, Y. (2025). Telmisartan mitigates behavioral and cytokine level alterations but impairs spatial working memory in a phencyclidine-induced mouse model of schizophrenia. Psychopharmacology.","DOI":"10.1007\/s00213-025-06805-y"}],"container-title":["Life"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2075-1729\/15\/8\/1333\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T18:33:22Z","timestamp":1760034802000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2075-1729\/15\/8\/1333"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,8,21]]},"references-count":79,"journal-issue":{"issue":"8","published-online":{"date-parts":[[2025,8]]}},"alternative-id":["life15081333"],"URL":"https:\/\/doi.org\/10.3390\/life15081333","relation":{},"ISSN":["2075-1729"],"issn-type":[{"value":"2075-1729","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,8,21]]}}}