Delayed administration of interleukin-1 receptor antagonist reduces ischemic brain damage and inflammation in comorbid rats
Delayed administration of interleukin-1 receptor antagonist reduces ischemic brain damage and inflammation in comorbid rats
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DOI：
10.1038/jcbfm.2012.101
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发表时间：
2012-09-01
影响因子：
6.3
通讯作者：
Allan, Stuart M.
中科院分区：
文献类型：
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作者：
Pradillo, Jesus M.;Denes, Adam;Allan, Stuart M.
许多神经保护剂对实验性中风有效，但很少转化为临床应用。其中一个原因可能是未能在实验模型中考虑临床合并症/风险因素。我们已经证明，一种自然产生的白介素1受体拮抗剂(IL-1ra)对健康动物的缺血性脑损伤具有保护作用。然而，IL-1ra在共病动物中的保护作用尚未确定。因此，我们测试了IL-1ra是否对具有临床相关危险因素的老年JCR-LA(肥胖)大鼠的实验性脑缺血所致的脑损伤具有保护作用。采用大脑中动脉短暂闭塞(TMCAO)模型，建立雄性、老年、消瘦和肥胖大鼠模型，在再灌注期间皮下注射两种剂量的IL-1ra(25 mg/kg)。TMCAO后24小时评价脑损伤和神经炎性改变。我们的结果表明，在再灌流时给予IL-1ra显著减少了磁共振成像测量的梗塞体积(50%，主要结果)和血脑屏障破坏。白介素1ra还减少了小胶质细胞的激活、中性粒细胞的渗透和脑组织中的细胞因子水平。这些数据首次表明，当IL-1ra通过临床相关的途径和时间窗在具有多种中风危险因素的动物身上使用时，可以预防缺血性脑损伤。《脑血流与代谢杂志》(2012年)32期，1810-1819年；doi：10.1038/jcbfm.2012.101；2012年7月11日在线出版
Many neuroprotective agents have been effective in experimental stroke, yet few have translated into clinical application. One reason for this may be failure to consider clinical comorbidities/risk factors in experimental models. We have shown that a naturally occurring interleukin-1 receptor antagonist (IL-1Ra) is protective against ischemic brain damage in healthy animals. However, protective effects of IL-1Ra have not been determined in comorbid animals. Thus, we tested whether IL-1Ra protects against brain injury induced by experimental ischemia in aged JCR-LA (corpulent) rats, which have clinically relevant risk factors. Male, aged, lean, and corpulent rats exposed to transient (90 minutes) occlusion of the middle cerebral artery (tMCAO) were administered two doses of IL-1Ra (25 mg/kg, subcutaneously) during reperfusion. Brain injury and neuroinflammatory changes were assessed 24 hours after tMCAO. Our results show that IL-1Ra administered at reperfusion significantly reduced infarct volume measured by magnetic resonance imaging (50%, primary outcome) and blood-brain barrier disruption in these comorbid animals. Interleukin-1Ra also reduced microglial activation, neutrophil infiltration, and cytokines levels in the brain. These data are the first to indicate that IL-1Ra protects against ischemic brain injury when administered via a clinically relevant route and time window in animals with multiple risk factors for stroke. Journal of Cerebral Blood Flow & Metabolism (2012) 32, 1810-1819; doi:10.1038/jcbfm.2012.101; published online 11 July 2012