{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,10]],"date-time":"2026-09-10T14:46:21Z","timestamp":1789051581197,"version":"build-2803163510"},"reference-count":88,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2021,5,10]],"date-time":"2021-05-10T00:00:00Z","timestamp":1620604800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003407","name":"Ministero dell\u2019Istruzione, dell\u2019Universit\u00e0 e della Ricerca","doi-asserted-by":"publisher","award":["2017XYBP2R"],"award-info":[{"award-number":["2017XYBP2R"]}],"id":[{"id":"10.13039\/501100003407","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Ischemic stroke is a leading cause of death and disability worldwide. The only pharmacological treatment available to date for cerebral ischemia is tissue plasminogen activator (t-PA) and the search for successful therapeutic strategies still remains a major challenge. The loss of cerebral blood flow leads to reduced oxygen and glucose supply and a subsequent switch to the glycolytic pathway, which leads to tissue acidification. Carbonic anhydrase (CA, EC 4.2.1.1) is the enzyme responsible for converting carbon dioxide into a protons and bicarbonate, thus contributing to pH regulation and metabolism, with many CA isoforms present in the brain. Recently, numerous studies have shed light on several classes of carbonic anhydrase inhibitor (CAI) as possible new pharmacological agents for the management of brain ischemia. In the present review we summarized pharmacological, preclinical and clinical findings regarding the role of CAIs in strokes and we discuss their potential protective mechanisms.<\/jats:p>","DOI":"10.3390\/ijms22095029","type":"journal-article","created":{"date-parts":[[2021,5,10]],"date-time":"2021-05-10T10:49:51Z","timestamp":1620643791000},"page":"5029","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":32,"title":["Role of Carbonic Anhydrase in Cerebral Ischemia and Carbonic Anhydrase Inhibitors as Putative Protective Agents"],"prefix":"10.3390","volume":"22","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4751-4434","authenticated-orcid":false,"given":"Irene","family":"Bulli","sequence":"first","affiliation":[{"name":"Department of Neuroscience, Psycology, Drug Research and Child Health (NEUROFARBA), Section of Pharmacology and Toxicology, University of Florence, 50139 Florence, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2766-470X","authenticated-orcid":false,"given":"Ilaria","family":"Dettori","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, Psycology, Drug Research and Child Health (NEUROFARBA), Section of Pharmacology and Toxicology, University of Florence, 50139 Florence, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4434-5919","authenticated-orcid":false,"given":"Elisabetta","family":"Coppi","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, Psycology, Drug Research and Child Health (NEUROFARBA), Section of Pharmacology and Toxicology, University of Florence, 50139 Florence, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6742-456X","authenticated-orcid":false,"given":"Federica","family":"Cherchi","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, Psycology, Drug Research and Child Health (NEUROFARBA), Section of Pharmacology and Toxicology, University of Florence, 50139 Florence, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martina","family":"Venturini","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, Psycology, Drug Research and Child Health (NEUROFARBA), Section of Pharmacology and Toxicology, University of Florence, 50139 Florence, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8374-4432","authenticated-orcid":false,"given":"Lorenzo","family":"Di Cesare Mannelli","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, Psycology, Drug Research and Child Health (NEUROFARBA), Section of Pharmacology and Toxicology, University of Florence, 50139 Florence, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carla","family":"Ghelardini","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, Psycology, Drug Research and Child Health (NEUROFARBA), Section of Pharmacology and Toxicology, University of Florence, 50139 Florence, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3342-702X","authenticated-orcid":false,"given":"Alessio","family":"Nocentini","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, Psycology, Drug Research and Child Health (NEUROFARBA), Section of Pharmaceutical Sciences, University of Florence, 50019 Florence, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4262-0323","authenticated-orcid":false,"given":"Claudiu T.","family":"Supuran","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, Psycology, Drug Research and Child Health (NEUROFARBA), Section of Pharmaceutical Sciences, University of Florence, 50019 Florence, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna Maria","family":"Pugliese","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, Psycology, Drug Research and Child Health (NEUROFARBA), Section of Pharmacology and Toxicology, University of Florence, 50139 Florence, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Felicita","family":"Pedata","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, Psycology, Drug Research and Child Health (NEUROFARBA), Section of Pharmacology and Toxicology, University of Florence, 50139 Florence, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,5,10]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"391","DOI":"10.1016\/S0166-2236(99)01401-0","article-title":"Pathobiology of ischaemic stroke: An integrated view","volume":"22","author":"Dirnagl","year":"1999","journal-title":"Trends Neurosci."},{"key":"ref_2","first-page":"467","article-title":"1026 Experimental treatments in acute stroke","volume":"59","author":"Macleod","year":"2006","journal-title":"Ann. Neurol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"268","DOI":"10.1212\/CON.0000000000000840","article-title":"Update on Treatment of acute ischemic stroke","volume":"26","author":"Rabinstein","year":"2020","journal-title":"Contin. Lifelong Learn. Neurol."},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Barthels, D., and Das, H. (2020). Current advances in ischemic stroke research and therapies. Biochim. Biophys. Acta-Mol. Basis Dis., 1866.","DOI":"10.1016\/j.bbadis.2018.09.012"},{"key":"ref_5","first-page":"29","article-title":"Heart disease and stroke statistics\u20142015 update","volume":"131","author":"Mozaffarian","year":"2015","journal-title":"Circulation"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1355","DOI":"10.1038\/jcbfm.2013.102","article-title":"Cerebral ischemic stroke: Is gender important?","volume":"33","author":"Gibson","year":"2013","journal-title":"J. Cereb. Blood Flow Metab."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"155","DOI":"10.1038\/jcbfm.1981.18","article-title":"Cell damage in the brain: A speculative synthesis","volume":"1","author":"Siesjo","year":"1981","journal-title":"J. Cereb. Blood Flow Metab."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"597","DOI":"10.1038\/jcbfm.1991.109","article-title":"Extracellular pH in the brain during ischemia: Relationship to the severity of lactic acidosis","volume":"11","author":"Katsura","year":"1991","journal-title":"J. Cereb. Blood Flow Metab."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"2489","DOI":"10.1523\/JNEUROSCI.11-08-02489.1991","article-title":"Acid-induced death in neurons and glia","volume":"11","author":"Nedergaard","year":"1991","journal-title":"J. Neurosci."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"4096","DOI":"10.1007\/s00330-018-5964-3","article-title":"Amide proton transfer\u2014Weighted MRI can detect tissue acidosis and monitor recovery in a transient middle cerebral artery occlusion model compared with a permanent occlusion model in rats","volume":"29","author":"Park","year":"2019","journal-title":"Eur. Radiol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"905","DOI":"10.1016\/j.neuint.2007.10.015","article-title":"Regulation of pH in the mammalian central nervous system under normal and pathological conditions: Facts and hypotheses","volume":"52","author":"Obara","year":"2008","journal-title":"Neurochem. Int."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/S0079-6123(08)63257-4","article-title":"Acidosis-related brain damage","volume":"96","author":"Katsura","year":"1993","journal-title":"Prog. Brain Res."},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Erra D\u00edaz, F., Dantas, E., and Geffner, J. (2018). Unravelling the interplay between extracellular acidosis and immune cells. Mediat. Inflamm., 2018.","DOI":"10.1155\/2018\/1218297"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"297","DOI":"10.1038\/jcbfm.1981.34","article-title":"Brain lactic acidosis and ischemic cell damage: I. biochemistry and neurophysiology","volume":"1","author":"Rehncrona","year":"1981","journal-title":"J. Cereb. Blood Flow Metab."},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"T\u00f3th, O.M., Menyh\u00e1rt, \u00c1., Frank, R., Hantosi, D., Farkas, E., and Bari, F. (2020). Tissue acidosis associated with ischemic stroke to guide neuroprotective drug delivery. Biology, 9.","DOI":"10.3390\/biology9120460"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"222","DOI":"10.1212\/WNL.33.2.222","article-title":"What causes infarction in ischemic brain? The Robert Wartenberg lecture","volume":"33","author":"Plum","year":"1983","journal-title":"Neurology"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"417","DOI":"10.1038\/jcbfm.1995.52","article-title":"Acidosis causes failure of astrocyte glutamate uptake during hypoxia","volume":"15","author":"Swanson","year":"1995","journal-title":"J. Cereb. Blood Flow Metab."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"168","DOI":"10.1038\/nrd2467","article-title":"Carbonic anhydrases: Novel therapeutic applications for inhibitors and activators","volume":"7","author":"Supuran","year":"2008","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Supuran, C.T. (2018). Applications of carbonic anhydrases inhibitors in renal and central nervous system diseases. Expert Opin. Ther. Pat., 1744\u20137674.","DOI":"10.1080\/13543776.2018.1519023"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"2485","DOI":"10.1002\/med.21713","article-title":"Progress in the development of human carbonic anhydrase inhibitors and their pharmacological applications: Where are we today?","volume":"40","author":"Mishra","year":"2020","journal-title":"Med. Res. Rev."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"345","DOI":"10.3109\/14756366.2015.1122001","article-title":"How many carbonic anhydrase inhibition mechanisms exist?","volume":"31","author":"Supuran","year":"2016","journal-title":"J. Enzyme Inhib. Med. Chem."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"561","DOI":"10.1080\/14756366.2021.1882453","article-title":"Reconsidering anion inhibitors in the general context of drug design studies of modulators of activity of the classical enzyme carbonic anhydrase","volume":"36","author":"Nocentini","year":"2021","journal-title":"J. Enzyme Inhib. Med. Chem."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"4389","DOI":"10.1016\/j.bmcl.2014.08.015","article-title":"Discovery of a new family of carbonic anhydrases in the malaria pathogen Plasmodium falciparum\u2014The \u03b7-carbonic anhydrases","volume":"24","author":"Vullo","year":"2014","journal-title":"Bioorgan. Med. Chem. Lett."},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Supuran, C.T. (2018). Carbonic anhydrase inhibitors and their potential in a range of therapeutic areas. Expert Opin. Ther. Pat., 709\u2013712.","DOI":"10.1080\/13543776.2018.1523897"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"717","DOI":"10.1517\/13543776.2013.782394","article-title":"Anticonvulsant\/antiepileptic carbonic anhydrase inhibitors: A patent review","volume":"23","author":"Aggarwal","year":"2013","journal-title":"Expert Opin. Ther. Pat."},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Berrino, E., and Carta, F. (2019). Carbonic anhydrase inhibitors for the treatment of epilepsy and obesity. Carbonic Anhydrases: Biochemistry and Pharmacology of an Evergreen Pharmaceutical Target, Elsevier.","DOI":"10.1016\/B978-0-12-816476-1.00015-0"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"855","DOI":"10.2174\/156802607780636726","article-title":"Carbonic anhydrase inhibitors as anticonvulsant agents","volume":"7","author":"Thiry","year":"2007","journal-title":"Curr. Top. Med. Chem."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1016\/j.neulet.2017.02.032","article-title":"Acetazolamide lowers intracranial pressure and modulates the cerebrospinal fluid secretion pathway in healthy rats","volume":"645","author":"Uldall","year":"2017","journal-title":"Neurosci. Lett."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"302","DOI":"10.1016\/j.pain.2009.11.015","article-title":"Acetazolamide and midazolam act synergistically to inhibit neuropathic pain","volume":"148","author":"Asiedu","year":"2010","journal-title":"Pain"},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Supuran, C.T. (2016). Carbonic anhydrase inhibition and the management of neuropathic pain. Expert Rev. Neurother., 961\u2013968.","DOI":"10.1080\/14737175.2016.1193009"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"929","DOI":"10.1016\/j.bbadis.2017.01.025","article-title":"Regulation of high glucose-induced apoptosis of brain pericytes by mitochondrial CA VA: A specific target for prevention of diabetic cerebrovascular pathology","volume":"1863","author":"Price","year":"2017","journal-title":"Biochim. Biophys. Acta-Mol. Basis Dis."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"452","DOI":"10.1124\/jpet.116.237057","article-title":"Blood-brain barrier disruption and neurovascular unit dysfunction in diabetic mice: Protection with the mitochondrial carbonic anhydrase inhibitor topiramate","volume":"359","author":"Salameh","year":"2016","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"165","DOI":"10.1111\/head.12997","article-title":"Topiramate in migraine prevention: A 2016 perspective","volume":"57","author":"Silberstein","year":"2017","journal-title":"Headache"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1016\/j.nbd.2015.11.006","article-title":"The carbonic anhydrase inhibitor methazolamide prevents amyloid beta-induced mitochondrial dysfunction and caspase activation protecting neuronal and glial cells in vitro and in the mouse brain","volume":"86","author":"Fossati","year":"2016","journal-title":"Neurobiol. Dis."},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"Angiulli, F., Solesio, M., Debure, L., Cejudo, J., Wisniewski, T., and Fossati, S. (2018). Carbonic anydrase inhibitors ameliorate neurovascular dysfunction in a mouse model of cerebral amyloid angiopathy. Alzheimer\u2019s Dement., 14.","DOI":"10.1016\/j.jalz.2018.06.1828"},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"Provensi, G., Carta, F., Nocentini, A., Supuran, C.T., Casamenti, F., Passani, M.B., and Fossati, S. (2019). A new kid on the block? Carbonic anhydrases as possible new targets in alzheimer\u2019s disease. Int. J. Mol. Sci., 20.","DOI":"10.3390\/ijms20194724"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"245","DOI":"10.1016\/0006-8993(94)01336-G","article-title":"Resistance of hippocampal synaptic transmission to hypoxia in carbonic anhydrase II-deficient mice","volume":"671","author":"Stanton","year":"1995","journal-title":"Brain Res."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1185","DOI":"10.1167\/iovs.05-0555","article-title":"Inhibition of apoptosis and reduction of intracellular pH decrease in retinal neural cell cultures by a blocker of carbonic anhydrase","volume":"47","author":"Kniep","year":"2006","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_39","first-page":"7075","article-title":"Hypoxia-inducible expression of tumor-associated carbonic anhydrases","volume":"60","author":"Wykoff","year":"2000","journal-title":"Cancer Res."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"23482","DOI":"10.1074\/jbc.M601719200","article-title":"Increased prolyl 4-hydroxylase domain proteins compensate for decreased oxygen levels: Evidence for an autoregulatory oxygen-sensing system","volume":"281","author":"Stiehl","year":"2006","journal-title":"J. Biol. Chem."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"689","DOI":"10.3109\/14756366.2014.966704","article-title":"Targeting tumour hypoxia to prevent cancer metastasis. From biology, biosensing and technology to drug development: The METOXIA consortium","volume":"30","author":"Pettersen","year":"2015","journal-title":"J. Enzyme Inhib. Med. Chem."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"428","DOI":"10.1007\/s12975-018-0663-6","article-title":"Acetazolamide mitigates intracranial pressure spikes without affecting functional outcome after experimental hemorrhagic stroke","volume":"10","author":"Williamson","year":"2019","journal-title":"Transl. Stroke Res."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"894","DOI":"10.3109\/14756366.2015.1113407","article-title":"Carbonic anhydrase inhibition for the management of cerebral ischemia: In vivo evaluation of sulfonamide and coumarin inhibitors","volume":"31","author":"Micheli","year":"2016","journal-title":"J. Enzyme Inhib. Med. Chem."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"252","DOI":"10.1016\/j.jocn.2020.01.079","article-title":"Collateral augmentation treatment with a combination of acetazolamide and head-down tilt in a rat ischemic stroke model","volume":"73","author":"Han","year":"2020","journal-title":"J. Clin. Neurosci."},{"key":"ref_45","doi-asserted-by":"crossref","unstructured":"Dettori, I., Fusco, I., Bulli, I., Gaviano, L., Coppi, E., Cherchi, F., Venturini, M., Di Cesare Mannelli, L., Ghelardini, C., and Nocentini, A. (2021). Protective effects of carbonic anhydrase inhibition in brain ischemia in vitro and in vivo models. J. Enzym. Inhib. Med. Chem., in press.","DOI":"10.1080\/14756366.2021.1907575"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"10692","DOI":"10.1021\/acs.jmedchem.6b01389","article-title":"Benzenesulfonamides incorporating flexible triazole moieties are highly effective carbonic anhydrase inhibitors: Synthesis and kinetic, crystallographic, computational, and intraocular pressure lowering investigations","volume":"59","author":"Nocentini","year":"2016","journal-title":"J. Med. Chem."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"510","DOI":"10.1080\/14756366.2018.1559840","article-title":"Phaeodactylum tricornutum as a model organism for testing the membrane penetrability of sulphonamide carbonic anhydrase inhibitors","volume":"34","author":"Rogato","year":"2019","journal-title":"J. Enzyme Inhib. Med. Chem."},{"key":"ref_48","doi-asserted-by":"crossref","unstructured":"Supuran, C.T. (2018). Carbonic Anhydrases and Metabolism. Metabolites, 8.","DOI":"10.3390\/metabo8020025"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"524","DOI":"10.1038\/sj.bjp.0706646","article-title":"A 3 adenosine receptor antagonists delay irreversible synaptic failure caused by oxygen and glucose deprivation in the rat CA1 hippocampus in vitro","volume":"147","author":"Pugliese","year":"2006","journal-title":"Br. J. Pharmacol."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"891","DOI":"10.1152\/jn.1997.78.2.891","article-title":"Mechanisms underlying the rapid depolarization produced by deprivation of oxygen and glucose in rat hippocampal CA1 neurons in vitro","volume":"78","author":"Tanaka","year":"1997","journal-title":"J. Neurophysiol."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"12","DOI":"10.1038\/jcbfm.1994.3","article-title":"Cortical negative DC deflections following middle cerebral artery occlusion and KCl-induced spreading depression: Effect on blood flow, tissue oxygenation, and electroencephalogram","volume":"14","author":"Back","year":"1994","journal-title":"J. Cereb. Blood Flow Metab."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"148","DOI":"10.1016\/S0006-8993(99)01859-4","article-title":"The nature of penumbral depolarizations following focal cerebral ischemia in the rat","volume":"842","author":"Nallet","year":"1999","journal-title":"Brain Res."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"1129","DOI":"10.1161\/01.STR.17.6.1129","article-title":"Cell density in the border zone around old small human brain infarcts","volume":"17","author":"Nedergaard","year":"1986","journal-title":"Stroke"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"214","DOI":"10.1097\/00004647-199603000-00005","article-title":"MR detection of cortical spreading depression immediately after focal ischemia in the rat","volume":"16","author":"Moseley","year":"1996","journal-title":"J. Cereb. Blood Flow Metab."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"367","DOI":"10.1097\/00004647-199605000-00003","article-title":"The use of in vivo fluorescence image sequences to indicate the occurrence and propagation of transient focal depolarizations in cerebral ischemia","volume":"16","author":"Strong","year":"1996","journal-title":"J. Cereb. Blood Flow Metab."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"83","DOI":"10.1016\/0304-3940(92)90141-S","article-title":"Lactate and pH change in close correlation in the extracellular space of the rat brain during cortical spreading depression","volume":"135","author":"Scheller","year":"1992","journal-title":"Neurosci. Lett."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"12","DOI":"10.1038\/jcbfm.1984.3","article-title":"Extracellular pH changes during spreading depression and cerebral ischemia: Mechanisms of brain pH regulation","volume":"4","author":"Mutch","year":"1984","journal-title":"J. Cereb. Blood Flow Metab."},{"key":"ref_58","doi-asserted-by":"crossref","unstructured":"Menyh\u00e1rt, \u00c1., Z\u00f6lei-Sz\u00e9n\u00e1si, D., Pusk\u00e1s, T., Makra, P., Orsolya, M.T., Szepes, B.E., T\u00f3th, R., Iv\u00e1nkovits-Kiss, O., Obrenovitch, T.P., and Bari, F. (2017). Spreading depolarization remarkably exacerbates ischemia-induced tissue acidosis in the young and aged rat brain. Sci. Rep., 7.","DOI":"10.1038\/s41598-017-01284-4"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"148","DOI":"10.18203\/2349-3933.ijam20170099","article-title":"The effect of acetazolamide on intracerebral hemorrhage in stoke patients","volume":"4","author":"Abbasi","year":"2017","journal-title":"Int. J. Adv. Med."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"241","DOI":"10.1002\/glia.20277","article-title":"Functional demonstration of surface carbonic anhydrase IV activity on rat astrocytes","volume":"53","author":"Svichar","year":"2006","journal-title":"Glia"},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"8247","DOI":"10.1523\/JNEUROSCI.20-22-08247.2000","article-title":"Interstitial carbonic anhydrase (CA) activity in brain is attributable to membrane-bound CA type IV","volume":"20","author":"Tong","year":"2000","journal-title":"J. Neurosci."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"1301","DOI":"10.3389\/fnins.2019.01301","article-title":"Energy dynamics in the brain: Contributions of astrocytes to Metabolism and pH homeostasis","volume":"13","author":"Deitmer","year":"2019","journal-title":"Front. Neurosci."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"281","DOI":"10.31887\/DCNS.2009.11.3\/mbelanger","article-title":"The role of astroglia in neuroprotection","volume":"11","author":"Magistretti","year":"2009","journal-title":"Dialogues Clin. Neurosci."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"138","DOI":"10.1016\/0006-8993(90)90670-7","article-title":"Selective vulnerability of cultured cortical glia to injury by extracellular acidosis","volume":"530","author":"Giffard","year":"1990","journal-title":"Brain Res."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1016\/S0197-0186(02)00211-5","article-title":"[3H]-DA release evoked by low pH medium and internal H+ accumulation in rat hypothalamic synaptosomes: Involvement of calcium ions","volume":"43","author":"Cannizzaro","year":"2003","journal-title":"Neurochem. Int."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"293","DOI":"10.1038\/sj.bjp.0705960","article-title":"Extracellular protons differentially potentiate the responses of native AMPA receptor subtypes regulating neurotransmitter release","volume":"144","author":"Pittaluga","year":"2005","journal-title":"Br. J. Pharmacol."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"314","DOI":"10.1016\/j.neuron.2013.11.011","article-title":"Optogenetic countering of glial acidosis suppresses glial glutamate release and ischemic brain damage","volume":"81","author":"Beppu","year":"2014","journal-title":"Neuron"},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"1065","DOI":"10.1152\/physrev.2001.81.3.1065","article-title":"Mechanisms of spreading depression and hypoxic spreading depression-like depolarization","volume":"81","author":"Somjen","year":"2001","journal-title":"Physiol. Rev."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"492","DOI":"10.1177\/0271678X17699224","article-title":"Carbonic anhydrase inhibitors modify intracellular pH transients and contractions of rat middle cerebral arteries during CO 2 \/HCO 3\u2013 fluctuations","volume":"38","author":"Rasmussen","year":"2018","journal-title":"J. Cereb. Blood Flow Metab."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"264","DOI":"10.1016\/j.freeradbiomed.2013.05.024","article-title":"Nrf2 activation: A potential strategy for the prevention of acute mountain sickness","volume":"63","author":"Lisk","year":"2013","journal-title":"Free Radic. Biol. Med."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"181","DOI":"10.1038\/nm1534","article-title":"Extracellular carbonic anhydrase mediates hemorrhagic retinal and cerebral vascular permeability through prekallikrein activation","volume":"13","author":"Gao","year":"2007","journal-title":"Nat. Med."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"130","DOI":"10.1007\/s12975-011-0106-0","article-title":"Inhibition of carbonic anhydrase reduces brain injury after intracerebral hemorrhage","volume":"3","author":"Guo","year":"2012","journal-title":"Transl. Stroke Res."},{"key":"ref_73","doi-asserted-by":"crossref","unstructured":"Hladky, S.B., and Barrand, M.A. (2016). Fluid and ion transfer across the blood-brain and blood-cerebrospinal fluid barriers; a comparative account of mechanisms and roles. Fluids Barriers CNS, 13.","DOI":"10.1186\/s12987-016-0040-3"},{"key":"ref_74","first-page":"177","article-title":"Two-dimensional crystal structure of aquaporin-4 bound to the inhibitor acetazolamide","volume":"65","author":"Kamegawa","year":"2016","journal-title":"Reprod. Syst. Sex. Disord."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"778","DOI":"10.1007\/s00467-006-0411-0","article-title":"Aquaporin-4 and brain edema","volume":"22","author":"Papadopoulos","year":"2007","journal-title":"Pediatr. Nephrol."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"781","DOI":"10.1080\/13543776.2019.1679117","article-title":"Carbonic anhydrase inhibition and the management of glaucoma: A literature and patent review 2013\u20132019","volume":"29","author":"Supuran","year":"2019","journal-title":"Expert Opin. Ther. Pat."},{"key":"ref_77","doi-asserted-by":"crossref","unstructured":"Bua, S., Nocentini, A., and Supuran, C.T. (2019). Carbonic anhydrase inhibitors as diuretics. Carbonic Anhydrases: Biochemistry and Pharmacology of an Evergreen Pharmaceutical Target, Elsevier.","DOI":"10.1016\/B978-0-12-816476-1.00014-9"},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"241","DOI":"10.1016\/j.emc.2017.01.002","article-title":"Advances in the prevention and treatment of high altitude illness","volume":"35","author":"Davis","year":"2017","journal-title":"Emerg. Med. Clin. N. Am."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"339","DOI":"10.5455\/medarh.2016.70.339-341","article-title":"Brain edema after ischaemic stroke","volume":"70","author":"Dostovic","year":"2016","journal-title":"Med. Arch."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"18","DOI":"10.1093\/bja\/57.1.18","article-title":"Brain oedema following brain ischaemia and the influence of therapy","volume":"57","author":"Klatzo","year":"1985","journal-title":"Br. J. Anaesth."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"280","DOI":"10.1111\/j.1651-2227.2007.00615.x","article-title":"Acetazolamide induces indomethacin and ischaemia-sensitive pial arteriolar vasodilation in the piglet","volume":"97","author":"Domoki","year":"2008","journal-title":"Acta Paediatr. Int. J. Paediatr."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"1634","DOI":"10.1172\/JCI111579","article-title":"Effect of acetazolamide on cerebral blood flow and cerebral metabolic rate for oxygen","volume":"74","author":"Vorstrup","year":"1984","journal-title":"J. Clin. Investig."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"65","DOI":"10.1016\/S0304-3940(01)02325-4","article-title":"Nitric oxide modulates cerebral blood flow stimulation by acetazolamide in the rat cortex: A laser doppler scanning study","volume":"315","author":"Tuettenberg","year":"2001","journal-title":"Neurosci. Lett."},{"key":"ref_84","doi-asserted-by":"crossref","unstructured":"Kiss, B., Dallinger, S., Findl, O., Rainer, G., Eichler, H.G., and Schmetterer, L. (1999). Acetazolamide-induced cerebral and ocular vasodilation in humans is independent of nitric oxide. Am. J. Physiol.-Regul. Integr. Comp. Physiol., 276.","DOI":"10.1152\/ajpregu.1999.276.6.R1661"},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"443","DOI":"10.1038\/sj.bjp.0703825","article-title":"In vivo evidence for KCa channel opening properties of acetazolamide in the human vasculature","volume":"132","author":"Pickkers","year":"2001","journal-title":"Br. J. Pharmacol."},{"key":"ref_86","doi-asserted-by":"crossref","unstructured":"Yu, H., Qi, G.L., Wang, J., Chen, L., Deng, Z., Zhao, Y.S., Lei, S.S., and Zhu, X.Q. (2016). Aquaporin 4 inhibition decreased synthesis of cytokines by acetazolamide in the hippocampus of rats with pentrazol-induced chronic epilepsy. Genet. Mol. Res., 15.","DOI":"10.4238\/gmr.15039012"},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"110","DOI":"10.1016\/j.cyto.2016.04.003","article-title":"Effect of acetazolamide on cytokines in rats exposed to high altitude","volume":"83","author":"Wang","year":"2016","journal-title":"Cytokine"},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"113","DOI":"10.1113\/jphysiol.1981.sp013938","article-title":"The location of carbonic anhydrase in relation to the blood-brain barrier at the medullary chemoreceptors of the cat","volume":"320","author":"Hanson","year":"1981","journal-title":"J. Physiol."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/9\/5029\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T05:58:39Z","timestamp":1760162319000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/9\/5029"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,5,10]]},"references-count":88,"journal-issue":{"issue":"9","published-online":{"date-parts":[[2021,5]]}},"alternative-id":["ijms22095029"],"URL":"https:\/\/doi.org\/10.3390\/ijms22095029","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,5,10]]}}}