Department of Pharmacology, State University of Maringá, CEP 87020-900, Maringá, Paraná, Brazil.
Brain Res Bull. 2010 Apr 5;81(6):631-40. doi: 10.1016/j.brainresbull.2009.12.012. Epub 2010 Jan 7.
The present study evaluated the effects of sildenafil using the 4-vessel occlusion (VO)/internal carotid artery (ICA) model of chronic cerebral hypoperfusion (HCC). We previously found that permanent, three-stage occlusion of the vertebral arteries (VA) and ICA, four-VO/ICA, with an interstage interval (ISI) of 7 days was innocuous and caused no structural or functional outcomes in rats. Therefore, before testing sildenafil, we evaluated how a reduction in the number of occlusion stages (from three stages to two) and a shortening of the ISI might impact the survival rate, capacity for learning and memory, and histomorphological integrity of the hippocampus. Survival decreased from 100% to 70%, 62%, and 0% as the ISI was shortened from 7 to 5, 4, or 3 days, respectively. Using the two shortest ISIs, sildenafil (0.75-3.0 mg/kg, p.o.) abolished the mortality rate by approximately 95%. Profound neurodegeneration occurred in the CA1, CA2, CA3, and CA4 hippocampal subfields after an ISI of 4 days. Despite this, however, memory performance was unaffected. Subsequently, sildenafil treatment reduced 4-VO/ICA-induced hippocampal damage. The present results suggest that sildenafil may be potentially beneficial in the treatment of chronic cerebral hypoperfusion. Further studies should examine the manner by which the chronic 4-VO/ICA model may effectively cause cognitive impairment, thus improving its applicability in testing the effects of drugs against structural and/or functional outcomes of chronic cerebral hypoperfusion.
本研究采用 4 血管闭塞（VO）/颈内动脉（ICA）慢性脑低灌注（HCC）模型评估西地那非的作用。我们之前发现，椎动脉（VA）和 ICA 的永久性、三阶段闭塞，四-VO/ICA，中间间隔（ISI）为 7 天是无害的，不会对大鼠造成结构或功能结果。因此，在测试西地那非之前，我们评估了减少闭塞阶段的数量（从三个阶段减少到两个阶段）和缩短 ISI 可能如何影响海马体的存活率、学习和记忆能力以及组织形态完整性。当 ISI 从 7 天缩短至 5、4 或 3 天时，存活率分别从 100%降至 70%、62%和 0%。使用最短的两个 ISI，西地那非（0.75-3.0 mg/kg，po）将死亡率降低了约 95%。在 ISI 为 4 天时，CA1、CA2、CA3 和 CA4 海马亚区发生严重的神经退行性变。然而，尽管如此，记忆性能并未受到影响。随后，西地那非治疗减轻了 4-VO/ICA 诱导的海马损伤。目前的结果表明，西地那非可能对慢性脑低灌注的治疗有潜在益处。进一步的研究应检查慢性 4-VO/ICA 模型如何有效地引起认知障碍，从而提高其在测试药物对慢性脑低灌注的结构和/或功能结果的影响的适用性。
