Pharmacological Inhibition of Carbonic Anhydrases with a Positively Charged Pyridinium Sulfonamide Phenocopies the Neuroprotective Effects of Genetic Ablation in a Murine Setting of Oxygen/glucose Deprivation Followed by Re-oxygenation and Is...

Overview

Journal Heliyon

Specialty Social Sciences

Date 2025 Mar 3

PMID 40028587

Authors

Sara Amiranda

Mariangela Succoio

Serenella Anzilotti

Ornella Cuomo

Tiziana Petrozziello

Valentina Tedeschi

Arianna Finizio

Giorgia Mele

Seppo Parkkila

Lucio Annunziato

Giuseppina De Simone

Giuseppe Pignataro

Agnese Secondo

Nicola Zambrano

Affiliations

Soon will be listed here.

Abstract

Carbonic anhydrases constitute a family of metalloenzymes vital for maintaining acid-base balance and regulating pH in physio-pathological processes. These findings suggest carbonic anhydrases as potential therapeutic targets for treating pH-associated disorders, including cerebral ischemia, to mitigate hypoxia- and reoxygenation-induced neuronal damage. A focus on carbonic anhydrase IX showed that ischemic stress altered subcellular distributions of this enzyme in rodent neuronal populations. Given the enzyme's canonical membrane localization, we implemented pharmacological inhibition using a membrane-impermeant sulfonamide inhibitor in neuronal models of brain ischemia. The treatments exerted neuroprotective effects on neurons from knockout mice. Moreover, administration of the sulfonamide inhibitor to rats subjected to transient middle cerebral artery occlusion decreased infarct volumes and improved neurological deficits. Our results support the involvement of carbonic anhydrase IX in postischemic damage and pave the way for possible pharmacological interventions with selective inhibitors in the management of brain ischemia.

References

Kniep E, Roehlecke C, Ozkucur N, Steinberg A, Reber F, Knels L . Inhibition of apoptosis and reduction of intracellular pH decrease in retinal neural cell cultures by a blocker of carbonic anhydrase. Invest Ophthalmol Vis Sci. 2006; 47(3):1185-92. DOI: 10.1167/iovs.05-0555. View

Sisalli M, Secondo A, Esposito A, Valsecchi V, Savoia C, Di Renzo G . Endoplasmic reticulum refilling and mitochondrial calcium extrusion promoted in neurons by NCX1 and NCX3 in ischemic preconditioning are determinant for neuroprotection. Cell Death Differ. 2014; 21(7):1142-9. PMC: 4207481. DOI: 10.1038/cdd.2014.32. View

Lemon N, Canepa E, Ilies M, Fossati S . Carbonic Anhydrases as Potential Targets Against Neurovascular Unit Dysfunction in Alzheimer's Disease and Stroke. Front Aging Neurosci. 2021; 13:772278. PMC: 8635164. DOI: 10.3389/fnagi.2021.772278. View

Rusciano G, Sasso E, Capaccio A, Zambrano N, Sasso A . Revealing membrane alteration in cellsoverexpressing CA IX and EGFR by Surface-Enhanced Raman Scattering. Sci Rep. 2019; 9(1):1832. PMC: 6372785. DOI: 10.1038/s41598-018-37997-3. View

Di Cesare Mannelli L, Micheli L, Carta F, Cozzi A, Ghelardini C, Supuran C . Carbonic anhydrase inhibition for the management of cerebral ischemia: in vivo evaluation of sulfonamide and coumarin inhibitors. J Enzyme Inhib Med Chem. 2015; 31(6):894-9. DOI: 10.3109/14756366.2015.1113407. View

Alterio V, Vitale R, Monti S, Pedone C, Scozzafava A, Cecchi A . Carbonic anhydrase inhibitors: X-ray and molecular modeling study for the interaction of a fluorescent antitumor sulfonamide with isozyme II and IX. J Am Chem Soc. 2006; 128(25):8329-35. DOI: 10.1021/ja061574s. View

Anzilotti S, Valente V, Brancaccio P, Franco C, Casamassa A, Lombardi G . Chronic exposure to l-BMAA cyanotoxin induces cytoplasmic TDP-43 accumulation and glial activation, reproducing an amyotrophic lateral sclerosis-like phenotype in mice. Biomed Pharmacother. 2023; 167:115503. DOI: 10.1016/j.biopha.2023.115503. View

Sanguigno L, Casamassa A, Funel N, Minale M, Riccio R, Riccio S . Triticum vulgare extract exerts an anti-inflammatory action in two in vitro models of inflammation in microglial cells. PLoS One. 2018; 13(6):e0197493. PMC: 6002026. DOI: 10.1371/journal.pone.0197493. View

Buanne P, Renzone G, Monteleone F, Vitale M, Monti S, Sandomenico A . Characterization of carbonic anhydrase IX interactome reveals proteins assisting its nuclear localization in hypoxic cells. J Proteome Res. 2012; 12(1):282-92. DOI: 10.1021/pr300565w. View

10.

Barbato C, Canu N, Zambrano N, Serafino A, Minopoli G, Ciotti M . Interaction of Tau with Fe65 links tau to APP. Neurobiol Dis. 2005; 18(2):399-408. DOI: 10.1016/j.nbd.2004.10.011. View

11.

Supuran C, Di Fiore A, Alterio V, Monti S, De Simone G . Recent advances in structural studies of the carbonic anhydrase family: the crystal structure of human CA IX and CA XIII. Curr Pharm Des. 2010; 16(29):3246-54. DOI: 10.2174/138161210793429841. View

12.

Bulli I, Dettori I, Coppi E, Cherchi F, Venturini M, Di Cesare Mannelli L . Role of Carbonic Anhydrase in Cerebral Ischemia and Carbonic Anhydrase Inhibitors as Putative Protective Agents. Int J Mol Sci. 2021; 22(9). PMC: 8126098. DOI: 10.3390/ijms22095029. View

13.

Kciuk M, Gielecinska A, Mujwar S, Mojzych M, Marciniak B, Drozda R . Targeting carbonic anhydrase IX and XII isoforms with small molecule inhibitors and monoclonal antibodies. J Enzyme Inhib Med Chem. 2022; 37(1):1278-1298. PMC: 9090362. DOI: 10.1080/14756366.2022.2052868. View

14.

Alterio V, Di Fiore A, DAmbrosio K, Supuran C, De Simone G . Multiple binding modes of inhibitors to carbonic anhydrases: how to design specific drugs targeting 15 different isoforms?. Chem Rev. 2012; 112(8):4421-68. DOI: 10.1021/cr200176r. View

15.

Wang Y, Zhang H, Ma T, Lu Y, Xie H, Wang W . Piezo1 mediates neuron oxygen-glucose deprivation/reoxygenation injury via Ca/calpain signaling. Biochem Biophys Res Commun. 2019; 513(1):147-153. DOI: 10.1016/j.bbrc.2019.03.163. View

16.

Pignataro G, Esposito E, Cuomo O, Sirabella R, Boscia F, Guida N . The NCX3 isoform of the Na+/Ca2+ exchanger contributes to neuroprotection elicited by ischemic postconditioning. J Cereb Blood Flow Metab. 2010; 31(1):362-70. PMC: 3049459. DOI: 10.1038/jcbfm.2010.100. View

17.

Sasso E, Vitale M, Monteleone F, Boffo F, Santoriello M, Sarnataro D . Binding of carbonic anhydrase IX to 45S rDNA genes is prevented by exportin-1 in hypoxic cells. Biomed Res Int. 2015; 2015:674920. PMC: 4352447. DOI: 10.1155/2015/674920. View

18.

Ema M, Taya S, Yokotani N, Sogawa K, Matsuda Y, Fujii-Kuriyama Y . A novel bHLH-PAS factor with close sequence similarity to hypoxia-inducible factor 1alpha regulates the VEGF expression and is potentially involved in lung and vascular development. Proc Natl Acad Sci U S A. 1997; 94(9):4273-8. PMC: 20712. DOI: 10.1073/pnas.94.9.4273. View

19.

Velisek L, Moshe S, Stanton P . Resistance of hippocampal synaptic transmission to hypoxia in carbonic anhydrase II-deficient mice. Brain Res. 1995; 671(2):245-53. DOI: 10.1016/0006-8993(94)01336-g. View

20.

Secondo A, Pignataro G, Ambrosino P, Pannaccione A, Molinaro P, Boscia F . Pharmacological characterization of the newly synthesized 5-amino-N-butyl-2-(4-ethoxyphenoxy)-benzamide hydrochloride (BED) as a potent NCX3 inhibitor that worsens anoxic injury in cortical neurons, organotypic hippocampal cultures, and ischemic.... ACS Chem Neurosci. 2015; 6(8):1361-70. DOI: 10.1021/acschemneuro.5b00043. View