Department of Emergency Medicine, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, 200233 Shanghai, China.
Department of Neurosurgery, Minhang Hospital, Fudan University, 201100 Shanghai, China.
Front Biosci (Landmark Ed). 2024 Oct 15;29(10):356. doi: 10.31083/j.fbl2910356.
As antioxidant and anti-inflammatory agents, carbonic anhydrase inhibitors can exert potentially useful therapeutic effects following central nervous system trauma, including intracerebral hemorrhage (ICH). However, the therapeutic efficacy of ethoxyzolamide (ETZ) as a novel carbonic anhydrase inhibitor for ICH has not yet been determined.
An autologous blood injection method was used to establish ICH models, which were then used to establish the effects of intraperitoneal injection of ETZ on ICH. Neuronal damage, apoptotic protein expression, oxidative and inflammatory factor content, microglia marker Iba-1 positivity, hepatic and renal pathological changes, and serum concentrations of hepatic and renal function indices were assessed by Nissl staining, western blotting, enzyme-linked immunosorbent assay (ELISA), immunohistochemistry, hematoxylin and eosin (HE) staining, and automatic biochemical analysis in brain tissues.
The ICH group showed massive hemorrhagic foci; significant increases in brain water content, modified mouse neurological deficit scoring (mNSS) score, pro-apoptotic protein expression, oxidative factors, pro-inflammatory factors, and Iba-1 positivity; and significant reductions in Nissl body size, anti-apoptotic protein expression, and antioxidant factors, all of which were reversed by ETZ in a dose-dependent manner. ETZ has a good biosafety profile with no significant burden on the human liver or kidneys. The Kelch-like ECH-associated protein 1 (Keap1)/nuclear factor erythroid 2-related factor 2 (Nrf2) pathway was mildly activated in ICH mice, and was further increased after ETZ injection. Molecular docking experiments revealed that ETZ could dock onto the Nrf2-binding domain of keap1.
ETZ, as a novel carbonic anhydrase inhibitor, further activated the Keap1/Nrf2 pathway by docking with the Nrf2-binding domain of keap1, thereby exerting antioxidant, anti-inflammatory, anti-apoptotic, and cerebral neuroprotective effects in ICH mice.
作为抗氧化剂和抗炎剂，碳酸酐酶抑制剂在中枢神经系统损伤后，包括脑出血（ICH），可能具有潜在的治疗作用。然而，新型碳酸酐酶抑制剂乙氧唑胺（ETZ）治疗 ICH 的疗效尚未确定。
采用自体血注入法建立 ICH 模型，然后采用腹腔注射 ETZ 观察其对 ICH 的影响。通过尼氏染色、Western blot、酶联免疫吸附试验（ELISA）、免疫组织化学、苏木精-伊红（HE）染色和自动生化分析评估脑内神经元损伤、凋亡蛋白表达、氧化和炎症因子含量、小胶质细胞标志物 Iba-1 阳性率、肝肾功能指标血清浓度、肝肾功能病理变化。
ICH 组可见大量出血灶；脑含水量、改良小鼠神经功能缺损评分（mNSS）评分、促凋亡蛋白表达、氧化因子、促炎因子、Iba-1 阳性率显著升高；尼氏小体大小、抗凋亡蛋白表达和抗氧化因子显著降低，这些均被 ETZ 呈剂量依赖性逆转。ETZ 具有良好的生物安全性，对肝肾功能无明显负担。ICH 小鼠的 Kelch 样 ECH 相关蛋白 1（Keap1）/核因子红细胞 2 相关因子 2（Nrf2）通路轻度激活，ETZ 注射后进一步增加。分子对接实验表明，ETZ 可与 Keap1 的 Nrf2 结合域结合，从而进一步激活该通路。
ETZ 作为一种新型碳酸酐酶抑制剂，通过与 Keap1 的 Nrf2 结合域结合，进一步激活 Keap1/Nrf2 通路，从而对 ICH 小鼠发挥抗氧化、抗炎、抗凋亡和脑神经保护作用。
