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Stroke is usually caused by the occlusion of a cerebral artery (ischemic stroke) and sometimes by a cerebral hemorrhage. It is the leading cause of hospitalisation and disability, and the second leading cause of death in Europe. It is therefore important to understand how stroke causes the death of brain cells so as to be able to develop ways of protecting the brain cells. It is also important to improve therapy for people with brain lesions.

Ischemic stroke and neonatal asphyxia

Many acute neurological conditions, including stroke and neonatal asphyxia, involve the death of neurons and other cells by a process called excitotoxicity, which means death by excessive activation. If you can protect neurons against excitotoxicity, you have a key to protecting the brain against the devastating effects of stroke, neonatal asphyxia and several other conditions. Scientists at the DNF are finding ways of doing just that.

In particular, they are studying the intracellular pathways causing excitotoxic neuron death, and have found that a new inhibitor of one of these pathways, developed by collaborators in the Lausanne University Hospital, gives strong protection in many situations of excitotoxicity, including animal models of ischemic stroke. A problem in the treatment of stroke is that neuroprotective drugs need to be effective even when given several hours after the stroke, which is rarely the case. But the present inhibitor protects in animal stroke models even when given unprecedentedly late (6 hours or more) after the stroke. Clinical trials are being initiated by the new company, Xigen, with whom the DNF researchers are in close collaboration. Despite the efficacy of the present inhibitor, current DNF research aims at developing a second generation inhibitor that will be still more effective. See J. Puyal/A. Truttmann.

The role of glial cells in brain ischemia

Brian ischemia is followed by both acute and prolonged inflammatory responses characterized by the production of soluble inflammatory mediators and by leukocyte infiltration into the brain. The parenchymal component of the inflammatory response, called neuroinflammation, involves primarily morphological and functional changes of glial cells: microglia, the brain's resident macrophages, and astrocytes.

Researchers at DNF have recently discovered that astrocytes release glutamate by a Ca2+-regulated exocytosis process. Can this process be altered and contribute to excitotoxicity in brain ischemia? In collaboration with a neurologist expert in ischemic accidents, Dr. L. Hirt at Lausanne University Hospital (CHUV), they are developing a new experimental approach combining molecular biology, production of fluorescent tools and dynamic cellular imaging in organotypic brain slices in order to get a real-time view of the inflammatory glial cell reaction to an ischemic insult. Use of a tandem-scanner confocal microscope allows both ultra-fast imaging of rapid signalling events and time-lapse recording of slower morphological changes. In particular, researchers are interested in comparing the dynamics of localized calcium increases and glutamate exocytosis from astrocytes in normal conditions and in the course of inflammatory transformation. This approach aims at clarifying early alterations of glial cell signalling in ischemia and may lead to new therapeutic strategies. See Bezzi.

In vivo imaging of neuronal plasticity after stroke

Most cases of stroke are followed by a period of functional recovery, due in part to changes in cortical areas connected with the damaged region, but these changes remain poorly understood. Until recently it has been impossible to study these alterations in the living brain in real-time. Using a model of sensory stroke, developed here in Lausanne, combined with multi-photon imaging in vivo allows us to visualise directly the effects of a central lesion on the brain's circuits. This will provide, for the first time, a unique opportunity to study in high resolution how cortical neurons respond when connected areas of the brain are damaged (Groups Welker).

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