Williams Jason A, Barreiro Christopher J, Nwakanma Lois U, Lange Mary S, Kratz Lisa E, Blue Mary E, Berrong Jennifer, Patel Nishant D, Gott Vincent L, Troncoso Juan C, Johnston Michael V, Baumgartner William A
Division of Cardiac Surgery, The Johns Hopkins Medical Institutions, Kennedy-Krieger Institute, Baltimore, Maryland, USA.
Ann Thorac Surg. 2006 Jun;81(6):2235-41; discussion 2241-2. doi: 10.1016/j.athoracsur.2005.12.060.
The anticonvulsant valproic acid (sodium valproate, Depacon) acts as a neuroprotectant in rodents, but has never been tested in larger animals. We used valproate in our canine model of hypothermic circulatory arrest to evaluate its neuroprotective benefit in complex cardiac surgical cases.
Thirteen dogs pretreated with valproate before 2 hours of hypothermic circulatory arrest survived for 24 hours (n = 7) or 72 hours (n = 6). Thirteen control animals (placebo only) also survived for 24 hours (n = 7) or 72 hours (n = 6) after hypothermic circulatory arrest. Blinded clinical neurologic evaluation was performed daily until sacrifice using the Pittsburgh Canine Neurologic Scoring System. Brains were harvested for blinded histopathologic analysis by a neuropathologist to determine the extent of apoptosis and necrosis in 11 brain regions (Total Brain Cell Death Score: 0 = normal, 99 = extensive neuronal death in all regions). Quantification of N-acetyl-aspartate, an established marker for brain injury, was performed with mass spectrometry.
Valproate dogs scored significantly better than control animals on clinical neurologic evaluation. Histopathologic examination revealed that valproate animals demonstrated less neuronal damage (by Total Brain Cell Death Score) than control animals at both 24 hours (16.4 versus 11.4; p = 0.03) and 72 hours (21.7 versus 17.7; p = 0.07). At 72 hours, the entorhinal cortex, an area involved with learning and memory, was significantly protected in valproate dogs (p < 0.05). Furthermore, the cortex, hippocampus, and cerebellum demonstrated preservation of near-normal N-acetyl-aspartate levels after valproate pretreatment.
These data demonstrate clinical, histologic, and biochemical improvements in dogs pretreated with valproate before hypothermic circulatory arrest. This commonly used drug may offer a promising new approach to neuroprotection during cardiac surgery.
抗惊厥药物丙戊酸（丙戊酸钠，德巴金）在啮齿动物中具有神经保护作用，但从未在大型动物中进行过测试。我们在犬类低温循环骤停模型中使用丙戊酸，以评估其在复杂心脏手术病例中的神经保护益处。
13只在低温循环骤停前2小时接受丙戊酸预处理的犬存活了24小时（n = 7）或72小时（n = 6）。13只对照动物（仅接受安慰剂）在低温循环骤停后也存活了24小时（n = 7）或72小时（n = 6）。每天使用匹兹堡犬神经评分系统进行盲法临床神经学评估，直至处死动物。由神经病理学家对大脑进行盲法组织病理学分析，以确定11个脑区的凋亡和坏死程度（全脑细胞死亡评分：0 = 正常，99 = 所有区域广泛神经元死亡）。使用质谱法对已确定的脑损伤标志物N-乙酰天门冬氨酸进行定量分析。
在临床神经学评估中，丙戊酸处理的犬得分明显高于对照动物。组织病理学检查显示，丙戊酸处理的动物在24小时（16.4对11.4；p = 0.03）和72小时（21.7对17.7；p = 0.07）时，神经元损伤（根据全脑细胞死亡评分）均低于对照动物。在72小时时，丙戊酸处理的犬的内嗅皮质（一个与学习和记忆有关的区域）得到了显著保护（p < 0.05）。此外，丙戊酸预处理后，皮质、海马体和小脑的N-乙酰天门冬氨酸水平保持在接近正常的水平。
这些数据表明，在低温循环骤停前接受丙戊酸预处理的犬在临床、组织学和生化方面均有改善。这种常用药物可能为心脏手术期间的神经保护提供一种有前景的新方法。
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