Progress in the identification of stroke-related genes: emerging new possibilities to develop concepts in stroke therapy.
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.
Lippoldt
Andrea
A
Department of Radiopharmaceuticals Research, Schering AG Berlin, Berlin, Germany. andrea.lippoldt@schering.de
Reichel
Andreas
A
Moenning
Ursula
U
D000818:Animals; D004195:Disease Models, Animal; D006801:Humans; D007249:Inflammation / Q000235:genetics / Q000503:physiopathology; D009416:Nerve Regeneration / Q000235:genetics*; D020521:Stroke / Q000235:genetics* / Q000503:physiopathology / Q000628:therapy