The arachidonic acid pathway metabolite 20-hydroxyeicosatetraenoic acid (20-HETE) contributes to ischemia/reperfusion brain injury. Inhibition of 20-HETE formation can protect the developing brain from global ischemia. Here, we examined whether treatment with the 20-HETE synthesis inhibitor N-hydroxy-N-4-butyl-2-methylphenylformamidine (HET0016) can protect the immature brain from traumatic brain injury (TBI). Male rats at postnatal day 9-10 underwent controlled cortical impact followed by intraperitoneal injection with vehicle or HET0016 (1 mg/kg, 5 min and 3 h post-injury). HET0016 decreased the lesion volume by over 50% at 3 days of recovery, and this effect persisted at 30 days as the brain matured. HET0016 decreased peri-lesion gene expression of proinflammatory cytokines (tumor necrosis factor-α [TNF-α], interleukin-1β [IL-1β]) at 1 day and increased reparative cytokine (IL-4, IL-10) expression at 3 days. It also partially preserved microglial ramified processes, consistent with less activation. HET0016 decreased contralateral hindlimb foot faults and improved outcome on the novel object recognition memory task 30 days after TBI. In cultured BV2 microglia, HET0016 attenuated the lipopolysaccharide-evoked increase in release of TNF-α. Our data show that HET0016 improves acute and long-term histologic and functional outcomes, in association with an attenuated neuroinflammatory response after contusion of an immature rat brain.

中文翻译：

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在小儿外伤性脑损伤的大鼠模型中，使用20-羟基己二酸四烯酸合成抑制剂可改善结果。

花生四烯酸途径代谢产物20-羟基二十碳四烯酸（20-HETE）有助于缺血/再灌注脑损伤。抑制20-HETE的形成可以保护发育中的大脑免受整体缺血的影响。在这里，我们检查了使用20-HETE合成抑制剂N-羟基-N-4-丁基-2-甲基苯基甲am（HET0016）的治疗是否可以保护未成熟的大脑免受颅脑外伤（TBI）。在出生后第9-10天对雄性大鼠进行可控的皮质冲击，然后腹腔内注射溶媒或HET0016（1 mg / kg，在受伤后5分钟和3小时内）。HET0016在恢复的3天时将病变体积减少了50％以上，并且随着大脑的成熟，这种效果在30天后一直持续。HET0016降低了促炎细胞因子（肿瘤坏死因子-α[TNF-α]，白细胞介素1β[IL-1β]）在1天时表达，而修复细胞因子（IL-4，IL-10）在3天时表达增加。它也部分保留了小胶质细胞分枝的过程，与较少的活化一致。TET后30天，HET0016减少了对侧后肢足部断层，并改善了新型对象识别记忆任务的结果。在培养的BV2小胶质细胞中，HET0016减弱了脂多糖引起的TNF-α释放增加。我们的数据显示，HET0016可改善急性和长期的组织学和功能结局，并伴有未成熟大鼠脑挫伤后神经炎症反应减弱。TET后30天，HET0016减少了对侧后肢足部断层，并改善了新型对象识别记忆任务的结果。在培养的BV2小胶质细胞中，HET0016减弱了脂多糖引起的TNF-α释放增加。我们的数据显示，HET0016可改善急性和长期的组织学和功能结局，并伴有未成熟大鼠脑挫伤后神经炎症反应减弱。TET后30天，HET0016减少了对侧后肢足部断层，并改善了新型对象识别记忆任务的结果。在培养的BV2小胶质细胞中，HET0016减弱了脂多糖引起的TNF-α释放增加。我们的数据显示，HET0016可改善急性和长期的组织学和功能性结局，并伴有未成熟大鼠脑挫伤后减弱的神经炎症反应。