Allan S M, Parker L C, Collins B, Davies R, Luheshi G N, Rothwell N J
School of Biological Sciences, 1.124 Stopford Building, University of Manchester, Oxford Road, Manchester, M13 9PT, United Kingdom.
Proc Natl Acad Sci U S A. 2000 May 9;97(10):5580-5. doi: 10.1073/pnas.090464197.
The cytokine IL-1 mediates diverse forms of neurodegeneration, but its mechanism of action is unknown. We have demonstrated previously that exogenous and endogenous IL-1 acts specifically in the rat striatum to dramatically enhance ischemic and excitotoxic brain damage and cause extensive cortical injury. Here we tested the hypothesis that this distant effect of IL-1 is mediated through polysynaptic striatal outputs to the cortex via the hypothalamus. We show that IL-1beta injected into the rat striatum with the excitotoxin alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (S-AMPA) caused increased expression of IL-1beta (mRNA and protein) mainly in the cortex where maximum injury occurs. Marked increases in IL-1beta mRNA and protein were also observed in the hypothalamus. S-AMPA, injected alone into the striatum, caused only localized damage, but administration of IL-1beta into either the striatum or the lateral hypothalamus immediately after striatal S-AMPA resulted in widespread cell loss throughout the ipsilateral cortex. Finally we showed that the cortical cell death produced by striatal coinjection of S-AMPA and IL-1beta was significantly reduced by administration of the IL-1 receptor antagonist into the lateral hypothalamus. These data suggest that IL-1beta can act in the hypothalamus to modify cell viability in the cortex. We conclude that IL-1-dependent pathways project from the striatum to the cortex via the hypothalamus and lead to cortical injury, and that these may contribute to a number of human neurological conditions including stroke and head trauma.
细胞因子白细胞介素-1（IL-1）介导多种形式的神经退行性变，但其作用机制尚不清楚。我们之前已经证明，外源性和内源性IL-1在大鼠纹状体中具有特异性作用，可显著增强缺血性和兴奋性毒性脑损伤，并导致广泛的皮质损伤。在此，我们检验了这样一种假说，即IL-1的这种远距离效应是通过纹状体经下丘脑向皮质的多突触输出介导的。我们发现，将IL-1β与兴奋性毒素α-氨基-3-羟基-5-甲基-4-异恶唑丙酸（S-AMPA）注入大鼠纹状体后，主要在发生最大损伤的皮质中，IL-1β（mRNA和蛋白质）的表达增加。在下丘脑中也观察到IL-1β mRNA和蛋白质显著增加。单独将S-AMPA注入纹状体仅引起局部损伤，但在纹状体注射S-AMPA后立即将IL-1β注入纹状体或下丘脑外侧，会导致同侧整个皮质广泛的细胞丢失。最后，我们表明，通过向下丘脑外侧注射IL-1受体拮抗剂，可显著减少纹状体联合注射S-AMPA和IL-1β所产生的皮质细胞死亡。这些数据表明，IL-1β可在下丘脑中发挥作用，改变皮质中的细胞活力。我们得出结论，IL-1依赖性通路从纹状体经下丘脑投射至皮质，导致皮质损伤，这可能与包括中风和头部创伤在内的多种人类神经疾病有关。
