Amiranda Sara, Succoio Mariangela, Anzilotti Serenella, Cuomo Ornella, Petrozziello Tiziana, Tedeschi Valentina, Finizio Arianna, Mele Giorgia, Parkkila Seppo, Annunziato Lucio, De Simone Giuseppina, Pignataro Giuseppe, Secondo Agnese, Zambrano Nicola
Dipartimento di Medicina molecolare e Biotecnologie mediche, Università degli Studi di Napoli Federico II, Napoli, Italy.
CEINGE Biotecnologie Avanzate Franco Salvatore S.C.aR.L., Napoli, Italy.
Heliyon. 2025 Feb 5;11(4):e42457. doi: 10.1016/j.heliyon.2025.e42457. eCollection 2025 Feb 28.
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.
碳酸酐酶构成了一类金属酶家族，对于维持酸碱平衡以及在生理病理过程中调节pH值至关重要。这些发现表明碳酸酐酶作为治疗与pH相关疾病（包括脑缺血）的潜在治疗靶点，以减轻缺氧和复氧诱导的神经元损伤。对碳酸酐酶IX的研究表明，缺血应激改变了该酶在啮齿动物神经元群体中的亚细胞分布。鉴于该酶典型的膜定位，我们在脑缺血的神经元模型中使用一种膜不透性磺酰胺抑制剂进行了药理抑制。这些治疗对来自基因敲除小鼠的神经元发挥了神经保护作用。此外，对短暂性大脑中动脉闭塞的大鼠给予磺酰胺抑制剂可减少梗死体积并改善神经功能缺损。我们的结果支持碳酸酐酶IX参与缺血后损伤，并为在脑缺血管理中使用选择性抑制剂进行可能的药理干预铺平了道路。
