Valproate administered after traumatic brain injury provides neuroprotection and improves cognitive function in rats.
Valproate administered after traumatic brain injury provides neuroprotection and improves cognitive function in rats.
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DOI：
10.1371/journal.pone.0011383
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发表时间：
2010-06-30
期刊：
影响因子：
3.7
通讯作者：
Moore AN
中科院分区：
文献类型：
--
作者：
Dash PK;Orsi SA;Zhang M;Grill RJ;Pati S;Zhao J;Moore AN
创伤性脑损伤（TBI）引发一系列复杂的神经化学和信号传导变化，其导致病理事件，包括神经元过度活跃、过量谷氨酸释放、炎症、血脑屏障（BBB）通透性增加和脑水肿、基因表达改变和神经元功能障碍。据信，药物组合或作用于多个靶点的单一药物可能是治疗TBI的有效策略。丙戊酸盐是一种广泛使用的抗癫痫药物，具有多种靶点，包括GABA转氨酶、电压门控钠通道、糖原合成酶激酶（GSK）-3和组蛋白脱乙酰酶（HDAC），因此可减轻多种TBI相关病理。使用啮齿动物TBI模型，我们检测了丙戊酸盐损伤后给药是否可以降低BBB通透性、减少神经损伤并改善认知结果。剂量-反应研究显示，全身给予400 mg/kg（i.p.），而不是15、30、60或100 mg/kg，增加海马中组蛋白H3和H4乙酰化，并降低GSK-3活性。损伤后30分钟给予400 mg/kg丙戊酸盐改善了BBB完整性，表现为伊文思蓝染料外渗减少。与其抑制GSK-3和HDAC的剂量反应一致，丙戊酸盐在400 mg/kg（而非100 mg/kg）剂量下可减少TBI相关的海马树突状细胞损伤，减少皮质挫伤体积，并改善运动功能和空间记忆。当给予选择性HDAC抑制剂SAHA（辛二酰苯胺异羟肟酸）时，未观察到这些行为改善。我们的研究结果表明，TBI后不久给予丙戊酸盐可具有神经保护作用。由于目前尚无经临床证实的可用于最大限度减少TBI后损害的干预措施，因此本报告的结果支持将丙戊酸盐作为急性治疗策略进行进一步试验。
Traumatic brain injury (TBI) initiates a complex series of neurochemical and signaling changes that lead to pathological events including neuronal hyperactivity, excessive glutamate release, inflammation, increased blood-brain barrier (BBB) permeability and cerebral edema, altered gene expression, and neuronal dysfunction. It is believed that a drug combination, or a single drug acting on multiple targets, may be an effective strategy to treat TBI. Valproate, a widely used antiepileptic drug, has a number of targets including GABA transaminase, voltage-gated sodium channels, glycogen synthase kinase (GSK)-3, and histone deacetylases (HDACs), and therefore may attenuate a number of TBI-associated pathologies. Using a rodent model of TBI, we tested if post-injury administration of valproate can decrease BBB permeability, reduce neural damage and improve cognitive outcome. Dose-response studies revealed that systemic administration of 400 mg/kg (i.p.), but not 15, 30, 60 or 100 mg/kg, increases histone H3 and H4 acetylation, and reduces GSK-3 activity, in the hippocampus. Thirty min post-injury administration of 400 mg/kg valproate improved BBB integrity as indicated by a reduction in Evans Blue dye extravasation. Consistent with its dose response to inhibit GSK-3 and HDACs, valproate at 400 mg/kg, but not 100 mg/kg, reduced TBI-associated hippocampal dendritic damage, lessened cortical contusion volume, and improved motor function and spatial memory. These behavioral improvements were not observed when SAHA (suberoylanilide hydroxamic acid), a selective HDAC inhibitor, was administered. Our findings indicate that valproate given soon after TBI can be neuroprotective. As clinically proven interventions that can be used to minimize the damage following TBI are not currently available, the findings from this report support the further testing of valproate as an acute therapeutic strategy.
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