Purinergic receptor stimulation reduces cytotoxic edema and brain infarcts in mouse induced by photothrombosis by energizing glial mitochondria

Wei Zheng, Lora Talley Watts, Deborah M. Holstein, Suresh I. Prajapati, Charles Keller, Eileen H. Grass, Christi A. Walter, James D. Lechleiter

Research output: Contribution to journalArticle

47 Citations (Scopus)

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 59 diphosphate (2-MeSADP), an agonist with high specificity for the purinergic receptor type 1 isoform (P2Y1R). 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 (IP3)-dependent Ca2+ 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.

Original languageEnglish (US)
Article numbere14401
JournalPLoS One
Volume5
Issue number12
DOIs
StatePublished - 2010
Externally publishedYes

Fingerprint

Purinergic Receptors
Mitochondria
infarction
astrocytes
Brain Edema
neuroglia
Neuroglia
Astrocytes
edema
Brain
mitochondria
Edema
brain
mice
Green Fluorescent Proteins
green fluorescent protein
lesions (animal)
Brain Infarction
Diphosphates
thrombosis

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Zheng, W., Watts, L. T., Holstein, D. M., Prajapati, S. I., Keller, C., Grass, E. H., ... Lechleiter, J. D. (2010). Purinergic receptor stimulation reduces cytotoxic edema and brain infarcts in mouse induced by photothrombosis by energizing glial mitochondria. PLoS One, 5(12), [e14401]. https://doi.org/10.1371/journal.pone.0014401

Purinergic receptor stimulation reduces cytotoxic edema and brain infarcts in mouse induced by photothrombosis by energizing glial mitochondria. / Zheng, Wei; Watts, Lora Talley; Holstein, Deborah M.; Prajapati, Suresh I.; Keller, Charles; Grass, Eileen H.; Walter, Christi A.; Lechleiter, James D.

In: PLoS One, Vol. 5, No. 12, e14401, 2010.

Research output: Contribution to journalArticle

Zheng, W, Watts, LT, Holstein, DM, Prajapati, SI, Keller, C, Grass, EH, Walter, CA & Lechleiter, JD 2010, 'Purinergic receptor stimulation reduces cytotoxic edema and brain infarcts in mouse induced by photothrombosis by energizing glial mitochondria', PLoS One, vol. 5, no. 12, e14401. https://doi.org/10.1371/journal.pone.0014401
Zheng, Wei ; Watts, Lora Talley ; Holstein, Deborah M. ; Prajapati, Suresh I. ; Keller, Charles ; Grass, Eileen H. ; Walter, Christi A. ; Lechleiter, James D. / Purinergic receptor stimulation reduces cytotoxic edema and brain infarcts in mouse induced by photothrombosis by energizing glial mitochondria. In: PLoS One. 2010 ; Vol. 5, No. 12.
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