Abstract：
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.
摘要：
脑缺血是中风的主要基础,如果不能及时恢复血液供应，两者都有共同的致病起源，会导致不可逆转的脑损伤。现有证据表明，碳酸酐酶（CA）抑制剂（CAI）可以通过腺苷酰环化酶-环磷酸腺苷（cAMP）途径赋予针对缺血再灌注（I/R）病理的治疗益处。我们假设CAI和cAMP激活可以增强针对I/R病症的治疗结果。在这次调查中,本研究使用短暂性全脑I/R(tGCI/R)模型评估了二氯苯甲酰胺(CAI)的潜力和cAMP对缺血再灌注损伤的作用.对瑞士白化病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。二氯苯甲酰胺(DCPA,20mg/kg）和/或毛喉素（cAMP激动剂，3mg/kg）在BCCAo/R后腹膜内（i.p.）施用14天。结果表明，tGCI/R损害了神经认知功能，并降低了大脑中cAMP和蛋白激酶A（PKA）的水平，DCPA和/或毛喉素（FSK）可以改善这些水平。DCPA和/或FSK减轻tGCI/R诱导的脑水肿，血脑屏障功能障碍,氧化亚硝基应激，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损伤的神经和生化参数。然而,DCPA和FSK联合显示对tGCI/R的治疗效果大大提高。因此,CA和cAMP提出了新的靶标，可以延缓短暂性脑缺血发作发展为全面中风。
