Lippoldt Andrea, Reichel Andreas, Moenning Ursula
Department of Radiopharmaceuticals Research, Schering AG Berlin, Berlin, Germany.
CNS Drugs. 2005;19(10):821-32. doi: 10.2165/00023210-200519100-00002.
Stroke is a very complex disease influenced by many risk factors: genetic, environmental and comorbidities, such as hypertension, diabetes mellitus, obesity and having had a previous stroke. Neuroprotective therapies that have been found to be successful in laboratory animals have failed to produce the same benefits in clinical trials. Currently, a re-analysis of the clinical trial failures is underway and new therapeutic approaches using the growing knowledge from neurogenesis and neuroinflammation studies, combined with the information from gene expression studies, are taking place. This review focuses on possible ways to identify therapeutic targets using the new discoveries in neuroinflammation and intrinsic regenerative mechanisms of the brain. Molecular events associated with ischaemia trigger an environment for inflammation. Within the ischaemic region and its penumbra, a battery of chemokines and cytokines are released, which have both detrimental and beneficial effects, depending on the specific timepoint after injury and the current activation status of microglia/macrophages. Preventive therapies and treatments for stroke may be established by identifying the genes that are responsible for the induction of those phenotypic changes of microglia/macrophages that switch them to become players in tissue repair and regeneration processes. To aid in the establishment of new target sources for novel therapeutic agents, animal stroke models should closely mimic stroke in humans. To do so, these models should take into account the various risk factors for stroke. For example, hypertensive animals have a more vulnerable blood-brain barrier that in turn may trigger a greater degree of damage after stroke. Furthermore, in aged animals an accelerated astrocytic and microglial reaction has been observed and the regenerative capacity of aged brains is not as high as young brains. Improvements in animal models may also help to ensure better success rates of potential therapies in clinical studies. Inflammation in the brain is a double-edged sword--characterised by the deleterious effect of nerve cell damage and nerve cell death, as well as the beneficial influence on regeneration. The major challenge to develop successful stroke therapies is to broaden the knowledge regarding the underlying pathologic processes and the intrinsic mechanisms of the brain to drive regenerative and plasticity-related changes. On this basis, new concepts can be created leading to better stroke therapy.
中风是一种受多种风险因素影响的非常复杂的疾病，这些因素包括遗传、环境和合并症，如高血压、糖尿病、肥胖以及既往有过中风病史。在实验动物中已被证明成功的神经保护疗法在临床试验中却未能产生同样的效果。目前，正在对临床试验失败的情况进行重新分析，并且正在采用基于神经发生和神经炎症研究中不断增长的知识，结合基因表达研究信息的新治疗方法。本综述重点关注利用神经炎症和大脑内在再生机制的新发现来确定治疗靶点的可能方法。与缺血相关的分子事件引发了炎症环境。在缺血区域及其半暗带内，一系列趋化因子和细胞因子被释放，根据损伤后的特定时间点以及小胶质细胞/巨噬细胞的当前激活状态，它们具有有害和有益的双重作用。通过识别那些负责诱导小胶质细胞/巨噬细胞表型变化从而使其转变为组织修复和再生过程参与者的基因，有可能确立中风的预防疗法和治疗方法。为了有助于建立新型治疗药物的新靶点来源，动物中风模型应紧密模拟人类中风情况。要做到这一点，这些模型应考虑到中风的各种风险因素。例如，高血压动物的血脑屏障更脆弱，这反过来可能在中风后引发更大程度的损伤。此外，在老年动物中已观察到星形胶质细胞和小胶质细胞反应加速，并且老年大脑的再生能力不如年轻大脑。动物模型的改进也可能有助于确保潜在疗法在临床研究中有更高的成功率。大脑中的炎症是一把双刃剑——其特征是神经细胞损伤和神经细胞死亡的有害影响以及对再生的有益影响。开发成功的中风疗法的主要挑战在于拓宽对潜在病理过程和大脑驱动再生及可塑性相关变化的内在机制的认识。在此基础上，可以形成新的概念，从而实现更好的中风治疗。
