Barone F C, Parsons A A
Department of Cardiovascular Pharmacology, SmithKline Beecham Pharmaceuticals, King of Prussia, PA 19406, USA.
Expert Opin Investig Drugs. 2000 Oct;9(10):2281-306. doi: 10.1517/13543784.9.10.2281.
The importance of cytokines, especially TNF-alpha and IL-1beta, are emphasised in the propagation and maintenance of the brain inflammatory response to injury. Much data supports the case that ischaemia and trauma elicit an inflammatory response in the injured brain. This inflammatory response consists of mediators (cytokines, chemokines and adhesion molecules) followed by cells (neutrophils early after the onset of brain injury and then a later monocyte infiltration). De novo upregulation of pro-inflammatory cytokines, chemokines and endothelial-leukocyte adhesion molecules occurs soon after focal ischaemia and trauma, as well as at the time when the tissue injury is evolving. The significance of this brain inflammatory response and its contribution to brain injury is now becoming more understood. In this review, we discuss the role of TNF-alpha and IL-1beta in traumatic and ischaemic brain injury and associated inflammation and the co-operative actions of chemokines and adhesion molecules in this process. We also address novel approaches to target cytokines and reduce the brain inflammatory response and thus brain injury, in stroke and neurotrauma. The mitogen-activated protein kinase (MAPK), p38, has been linked to inflammatory cytokine production and cell death following cellular stress. Stroke-induced p38 enzyme activation in the brain has been demonstrated and treatment with a second generation p38 MAPK inhibitor, SB-239063, provides a significant reduction in infarct size, neurological deficits and inflammatory cytokine expression produced by focal stroke. SB-239063 can also provide direct protection of cultured brain tissue to in vitro ischaemia. This robust SB-239063-induced neuroprotection emphasises a significant opportunity for targeting MAPK pathways in ischaemic stroke injury and also suggests that p38 inhibition should be evaluated for protective effects in other experimental models of nervous system injury and neurodegeneration.
细胞因子，尤其是肿瘤坏死因子-α（TNF-α）和白细胞介素-1β（IL-1β），在脑损伤炎症反应的传播和维持中具有重要作用。大量数据表明，缺血和创伤会在受损大脑中引发炎症反应。这种炎症反应由介质（细胞因子、趋化因子和黏附分子）以及细胞组成（脑损伤发作后早期为中性粒细胞，随后是单核细胞浸润）。促炎细胞因子、趋化因子和内皮细胞-白细胞黏附分子在局灶性缺血和创伤后不久以及组织损伤进展时会重新上调。这种脑炎症反应的重要性及其对脑损伤的作用现在越来越清楚。在本综述中，我们讨论了TNF-α和IL-1β在创伤性和缺血性脑损伤及相关炎症中的作用，以及趋化因子和黏附分子在此过程中的协同作用。我们还探讨了针对细胞因子以减少脑炎症反应从而减轻脑损伤的新方法，这些方法适用于中风和神经创伤。丝裂原活化蛋白激酶（MAPK）中的p38与细胞应激后的炎症细胞因子产生和细胞死亡有关。已经证实中风会导致脑中p38酶激活，使用第二代p38 MAPK抑制剂SB-239063进行治疗可显著减小局灶性中风产生的梗死体积、神经功能缺损以及炎症细胞因子表达。SB-239063还可以直接保护培养的脑组织免受体外缺血的影响。这种由SB-239063强力诱导的神经保护作用凸显了针对缺血性中风损伤中的MAPK途径的重大机会，也表明应在其他神经系统损伤和神经退行性变的实验模型中评估p38抑制的保护作用。
