title: Purinergic receptor stimulation reduces cytotoxic edema and brain infarcts in mouse induced by photothrombosis by energizing glial mitochondria.
abstract: 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.
authors.affiliation: Department of Cellular and Structural Biology, University of Texas Health Science Center at San Antonio, San Antonio, Texas, United States of America.
authors.forename: Wei
authors.initials: W
authors.lastname: Zheng
authors.forename: Lora Talley
authors.initials: LT
authors.lastname: Watts
authors.forename: Deborah M
authors.initials: DM
authors.lastname: Holstein
authors.forename: Suresh I
authors.initials: SI
authors.lastname: Prajapati
authors.forename: Charles
authors.initials: C
authors.lastname: Keller
authors.forename: Eileen H
authors.initials: EH
authors.lastname: Grass
authors.forename: Christi A
authors.initials: CA
authors.lastname: Walter
authors.forename: James D
authors.initials: JD
authors.lastname: Lechleiter
mesh_terms: D000244:Adenosine Diphosphate / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D001253:Astrocytes / Q000166:cytology / Q000378:metabolism; D020520:Brain Infarction / Q000378:metabolism*; D002544:Cerebral Infarction / Q000473:pathology; D004487:Edema / Q000378:metabolism*; D015544:Inositol 1,4,5-Trisphosphate / Q000378:metabolism; D008027:Light; D008297:Male; D051379:Mice; D008928:Mitochondria / Q000378:metabolism*; D009457:Neuroglia / Q000378:metabolism*; D011983:Receptors, Purinergic / Q000378:metabolism*; D058472:Receptors, Purinergic P2Y1 / Q000378:metabolism; D013873:Thionucleotides / Q000494:pharmacology; D013927:Thrombosis / Q000378:metabolism*
chemical_list: D011983:Receptors, Purinergic; D058472:Receptors, Purinergic P2Y1; D013873:Thionucleotides; C002480:methylthio-ADP; D000244:Adenosine Diphosphate; D015544:Inositol 1,4,5-Trisphosphate