Ismael Saifudeen, Patrick Devlin, Salman Mohd, Parveen Arshi, Stanfill Ansley Grimes, Ishrat Tauheed
Department of Anatomy and Neurobiology, College of Medicine, The University of Tennessee Health Science Center, Memphis, TN, USA.
Department of Anatomy and Neurobiology, College of Medicine, The University of Tennessee Health Science Center, Memphis, TN, USA; Department of Acute and Tertiary Care, College of Nursing, University of Tennessee Health Science Center, Memphis, TN, USA.
Neurochem Int. 2022 Dec;161:105423. doi: 10.1016/j.neuint.2022.105423. Epub 2022 Oct 14.
Intracerebral hemorrhage (ICH) is the second most common type of stroke with no satisfactory treatment. Recent studies from our group and others indicated a potential positive effect of verapamil, a commonly prescribed calcium channel blocker, with thioredoxin-interacting protein (TXNIP) inhibitor properties, in ischemic stroke and cognitive disorders. It is unclear whether there would be a beneficial effect of verapamil administration in ICH. Therefore, this study was designed to determine the neuroprotective effects of verapamil in a murine ICH model. ICH was induced by stereotactic injection of collagenase type VII (0.075 U) into the right striatum of adult male C57BL/6 mice. Verapamil (0.15 mg/kg) or saline was administered intravenously at 1 h post-ICH followed by oral (1 mg/kg/d) administration in drinking water for 28 days. Motor and cognitive function were assessed using established tests for motor coordination, spatial learning, short- and long-term memory. A subset of animals was sacrificed at 72 h after ICH for molecular analysis. Verapamil treatment reduced expression of TXNIP and NOD-like receptor pyrin domain-containing-3 inflammasome activation in the perihematomal area. These protective effects of verapamil were associated with decreased proinflammatory mediators, microglial activation, and blood-brain barrier permeability markers and paralleled less phosphorylated nuclear factor kappa B level. Our findings also demonstrate that long-term low-dose verapamil effectively attenuated motor and cognitive impairments. Taken together, these data indicate that verapamil has therapeutic potential in improving acute motor function after ICH. Further investigations are needed to confirm whether verapamil treatment could be a promising candidate for clinical trials.
脑出血（ICH）是第二常见的中风类型，目前尚无令人满意的治疗方法。我们团队和其他团队最近的研究表明，维拉帕米（一种常用的钙通道阻滞剂，具有硫氧还蛋白相互作用蛋白（TXNIP）抑制特性）对缺血性中风和认知障碍具有潜在的积极作用。目前尚不清楚维拉帕米给药对脑出血是否有有益效果。因此，本研究旨在确定维拉帕米在小鼠脑出血模型中的神经保护作用。通过立体定向向成年雄性C57BL/6小鼠的右侧纹状体注射VII型胶原酶（0.075 U）诱导脑出血。在脑出血后1小时静脉注射维拉帕米（0.15 mg/kg）或生理盐水，随后在饮用水中口服（1 mg/kg/d）给药28天。使用既定的运动协调、空间学习、短期和长期记忆测试评估运动和认知功能。在脑出血后72小时处死一部分动物进行分子分析。维拉帕米治疗降低了血肿周围区域TXNIP的表达和含NOD样受体吡啉结构域的3炎性小体激活。维拉帕米的这些保护作用与促炎介质减少、小胶质细胞激活和血脑屏障通透性标志物降低有关，同时磷酸化核因子κB水平也较低。我们的研究结果还表明，长期低剂量维拉帕米可有效减轻运动和认知障碍。综上所述，这些数据表明维拉帕米在改善脑出血后的急性运动功能方面具有治疗潜力。需要进一步研究以确认维拉帕米治疗是否可能成为临床试验的有前景候选药物。
