Treatments to improve the neurological outcome of
edema and cerebral
ischemic stroke are severely limited. Here, we present the first in vivo single cell images of cortical mouse astrocytes documenting the impact of single vessel photothrombosis on cytotoxic
edema and
cerebral infarcts. The volume of astrocytes expressing
green fluorescent protein (GFP) increased by over 600% within 3 hours of
ischemia. The subsequent growth of
cerebral infarcts was easily followed as the loss of GFP fluorescence as astrocytes lysed. Cytotoxic
edema and the magnitude of ischemic lesions were significantly reduced by treatment with the purinergic
ligand 2-methylthioladenosine 5'
diphosphate (2-MeSADP), an agonist with high specificity for the
purinergic receptor type 1
isoform (P2Y(1)R). At 24 hours, cytotoxic
edema in astrocytes was still apparent at the penumbra and preceded the cell lysis that defined the
infarct. Delayed
2MeSADP treatment, 24 hours after the initial
thrombosis, also significantly reduced cytotoxic
edema and the continued growth of the
brain infarction. Pharmacological and genetic evidence are presented indicating that
2MeSADP protection is mediated by enhanced astrocyte mitochondrial metabolism via increased
inositol trisphosphate (IP(3))-dependent Ca(2+) release. We suggest that mitochondria play a critical role in astrocyte energy metabolism in the penumbra of ischemic lesions, where low
ATP levels are widely accepted to be responsible for cytotoxic
edema. Enhancement of this energy source could have similar protective benefits for a wide range of
brain injuries.