Stroke – University of Copenhagen

Stroke

Cerebral Ischemic stroke is a leading neurological disorder that causes severe brain damage, disability and mortality. Despite decades of effort into developing effective therapies for stroke, the treatment strategies available are unable to prevent progression of damage cause by cerebral ischemic lesion (or stroke) in the acutely injured human brain. Moreover, neuroprotective drugs which, have been validated in preclinical models have failed to achieve desirable clinical benefits in clinical trials. Identifying new molecular pathways and mechanisms that underlie the progression of pathology in injured human brain post-stroke is vital in developing effective therapies to treat this disorder.

Recent studies suggest that restoring the integrity of the so called “Extended Neurovascular unit” is therapeutically vital for the successful treatment of ischemic stroke. The neurovascular unit is a functional and structurally interdependent multi-cellular complex, comprised of endothelial cells, the basal lamina, pericytes, astrocytes, and neurons. Dysfunction of the neurovascular unit is associated with a reduction in cerebral blood flow (CBF) and hypoxia ultimately leading to neuronal death.  Studies have shown that in stroke neurovascular dysfunction prevails outside the ischemic core, in the penumbral area (the region that is immediately adjacent to the core with less severe blood perfusion deficits), however the underlying molecular mechanisms are not completely understood.

Astrocytes regulate neuronal function, synaptic plasticity and cerebral blood flow by elevations in Ca2+ concentrations in soma as well as in their cellular processes. Further, brain astrocytes use Ca2+ waves (ACW’s) as a means for communicating with each other and with other cell-types. Recent studies have suggested that the occurrence of spontaneous glial Ca2+ waves (ACW’s) was 20-fold higher in the cortex of aging brain as compared to the adult brain and that increased Ca2+ waves in astrocytes correlated with the reduction in resting brain oxygen tension suggesting a relationship between glial waves, brain energy homeostatic and pathology.

Laser speckle imaging of the brain before and after stroke. Healthy tissue (CBF >50 % of pre-stroke values) shown in gray scales. Peri-ischemic area shown in blue and ischemic core (CBF <20 % of pre-stroke values) in purple. Each panel corresponds to different times relative to stroke. Black scale bar = 1 mm.


In this study, we hypothesize that glial Ca2+ signals (both in the form of transients Ca2+ elevations and ACW’s) might represent the underlying mechanisms of damage in ischemic penumbra in stroke.  By using state-of-the-art two-photon Ca2+ imaging and electrophysiology, we aim to examine astroglial Ca2+ signals and waves and its impact on neuronal function in a mouse model of stroke (middle cerebral occlusion model).

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