title: P2Y1R-initiated, IP3R-dependent stimulation of astrocyte mitochondrial metabolism reduces and partially reverses ischemic neuronal damage in mouse.
abstract: Glia-based neuroprotection strategies are emerging as promising new avenues to treat brain damage. We previously reported that activation of the glial-specific purinergic receptor, P2Y(1)R, reduces both astrocyte swelling and brain infarcts in a photothrombotic mouse model of stroke. These restorative effects were dependent on astrocyte mitochondrial metabolism. Here, we extend these findings and report that P2Y(1)R stimulation with the purinergic ligand 2-methylthioladenosine 5' diphosphate (2MeSADP) reduces and partially reverses neuronal damage induced by photothrombosis. In vivo neuronal morphology was confocally imaged in transgenic mice expressing yellow fluorescent protein under the control of the Thy1 promoter. Astrocyte mitochondrial membrane potentials, monitored with the potential sensitive dye tetra-methyl rhodamine methyl ester, were depolarized after photothrombosis and subsequently repolarized when P2Y(1)Rs were stimulated. Mice deficient in the astrocyte-specific type 2 inositol 1,4,5 trisphosphate (IP(3)) receptor exhibited aggravated ischemic dendritic damage after photothrombosis. Treatment of these mice with 2MeSADP did not invoke an intracellular Ca(2+) response, did not repolarize astrocyte mitochondria, and did not reduce or partially reverse neuronal lesions induced by photothrombotic stroke. These results demonstrate that IP(3)-Ca(2+) signaling in astrocytes is not only critical for P2Y(1)R-enhanced protection, but suggest that IP(3)-Ca(2+) signaling is also a key component of endogenous neuroprotection.
authors: Department of Cellular and Structural Biology, San Antonio, TX, USA.
authors: Wei
authors: W
authors: Zheng
authors: Lora
authors: L
authors: Talley Watts
authors: Deborah M
authors: DM
authors: Holstein
authors: Jimmy
authors: J
authors: Wewer
authors: James D
authors: JD
authors: Lechleiter
mesh_terms: D000244:Adenosine Diphosphate / Q000031:analogs & derivatives / Q000494:pharmacology*; D000818:Animals; D001253:Astrocytes / Q000378:metabolism* / Q000473:pathology; D002545:Brain Ischemia / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D020013:Calcium Signaling / Q000187:drug effects / Q000235:genetics; D003712:Dendrites / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D053496:Inositol 1,4,5-Trisphosphate Receptors / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D058912:Purinergic P2Y Receptor Agonists / Q000494:pharmacology*; D058472:Receptors, Purinergic P2Y1 / Q000235:genetics / Q000378:metabolism*
chemical_list: D053496:Inositol 1,4,5-Trisphosphate Receptors; D058912:Purinergic P2Y Receptor Agonists; D058472:Receptors, Purinergic P2Y1; D000244:Adenosine Diphosphate