Cerebral ischemia is the primary basis of stroke, both sharing common pathogenic origins leading to irreversible brain damage if blood supply is not restored promptly. Existing evidence indicates that carbonic anhydrase (CA) inhibitors (CAIs) may impart therapeutic benefits against ischemia–reperfusion (I/R) pathology via the adenylyl cyclase-cyclic adenosine monophosphate (cAMP) pathway. We hypothesize that CAI and cAMP activation may enhance the therapeutic outcome against I/R conditions. In this investigation, the potential of dichlorphenamide (CAI) and the role of cAMP against ischemia–reperfusion injury were evaluated using a transient global cerebral I/R (tGCI/R) model. Swiss albino mice were subjected to bilateral common carotid artery occlusion (BCCAo) for 20 min and reperfusion (R) or sham surgery on day 1. Dichlorphenamide (DCPA, 20 mg/kg) and/or forskolin (cAMP agonist, 3 mg/kg) was administered intraperitoneally (i.p.) after BCCAo/R for 14 days. Results showed that tGCI/R impaired neurocognitive functions and lowered brain levels of cAMP and protein kinase A (PKA) that were ameliorated by DCPA and/or forskolin (FSK). DCPA and/or FSK attenuated tGCI/R-induced brain edema, blood–brain barrier dysfunction, oxidative-nitrosative stress, pro-inflammatory cytokines, acetylcholinesterase activity, cell death, and neurotransmitter imbalance (e.g., glutamate, γ-aminobutyric acid). The study showed that DCPA improved neurological and biochemical parameters against tGCI/R injury via cAMP-PKA-mediated activation of protective mechanisms. However, DCPA and FSK in combination showed much enhanced therapeutic outcomes against tGCI/R. Therefore, CA and cAMP present novel targets that may retard the progress of a transient ischemic attack to a full-blown stroke.

脑缺血是中风的主要原因，两者具有共同的致病根源，如果血液供应不能及时恢复，就会导致不可逆的脑损伤。现有证据表明碳酸酐酶 (CA) 抑制剂 (CAI) 可能通过腺苷酸环化酶-环磷酸腺苷 (cAMP) 途径对缺血再灌注 (I/R) 病理学产生治疗效果。我们假设 CAI 和 cAMP 激活可能会增强 I/R 病症的治疗效果。在这项研究中，使用短暂性全脑 I/R (tGCI/R) 模型评估了二氯苯酰胺 (CAI) 的潜力和 cAMP 抗缺血再灌注损伤的作用。对瑞士白化小鼠进行双侧颈总动脉闭塞 (BCCAo) 20 分钟，并在第 1 天进行再灌注 (R) 或假手术。ip ) BCCAo/R 后 14 天。结果表明，tGCI/R 会损害神经认知功能，并降低大脑中 cAMP 和蛋白激酶 A (PKA) 的水平，而 DCPA 和/或毛喉素 (FSK) 可以改善这种情况。DCPA和/或FSK减轻tGCI/R引起的脑水肿、血脑屏障功能障碍、氧化亚硝化应激、促炎细胞因子、乙酰胆碱酯酶活性、细胞死亡和神经递质失衡（例如谷氨酸、γ-氨基丁酸）。研究表明，DCPA 通过 cAMP-PKA 介导的保护机制激活，改善了针对 tGCI/R 损伤的神经学和生化参数。然而，DCPA 和 FSK 联合使用对 tGCI/R 的治疗效果显着增强。因此，CA 和 cAMP 是可能延缓短暂性脑缺血发作发展为全面中风的新靶点。