title: Purinergic 2Y1 receptor stimulation decreases cerebral edema and reactive gliosis in a traumatic brain injury model.
abstract: Traumatic brain injury (TBI) is the leading cause of death and disability in children and young adults. Neuroprotective agents that may promote repair or counteract damage after injury do not currently exist. We recently reported that stimulation of the purinergic receptor subtype P2Y(1)R using 2-methylthioladenosine 5' diphosphate (2MeSADP) significantly reduced cytotoxic edema induced by photothrombosis. Here, we tested whether P2Y(1)R stimulation was neuroprotective after TBI. A controlled closed head injury model was established for mice using a pneumatic impact device. Brains were harvested at 1, 3, or 7 days post-injury and assayed for morphological changes by immunocytochemistry, Western blot analysis, and wet/dry weight. Cerebral edema and expression of both aquaporin type 4 and glial fibrillary acidic protein were increased at all time points examined. Immunocytochemical measurements in both cortical and hippocampal slices also revealed significant neuronal swelling and reactive gliosis. Treatment of mice with 2MeSADP (100 μM) or MRS2365 (100 μM) 30 min after trauma significantly reduced all post-injury symptoms of TBI including edema, neuronal swelling, reactive gliosis, and AQ4 expression. The neuroprotective effect was lost in IP(3)R2-/- mice treated with 2MeSADP. Immunocytochemical labeling of brain slices confirmed that P2Y(1)R expression was defined to cortical and hippocampal astrocytes, but not neurons. Taken together, the data show that stimulation of astrocytic P2Y(1)Rs significantly reduces brain injury after acute trauma and is mediated by the IP(3)-signaling pathway. We suggest that enhancing astrocyte mitochondrial metabolism offers a promising neuroprotective strategy for a broad range of brain injuries.
authors.affiliation: Department of Cellular and Structural Biology, The University of Texas Health Science Center at San Antonio School of Medicine, TX 78229-3904, USA.
authors.forename: Lora
authors.initials: L
authors.lastname: Talley Watts
authors.forename: Shane
authors.initials: S
authors.lastname: Sprague
authors.forename: Wei
authors.initials: W
authors.lastname: Zheng
authors.forename: R Justin
authors.initials: RJ
authors.lastname: Garling
authors.forename: David
authors.initials: D
authors.lastname: Jimenez
authors.forename: Murat
authors.initials: M
authors.lastname: Digicaylioglu
authors.forename: James
authors.initials: J
authors.lastname: Lechleiter
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000378:metabolism* / Q000473:pathology; D001929:Brain Edema / Q000209:etiology / Q000378:metabolism* / Q000517:prevention & control*; D001930:Brain Injuries / Q000150:complications / Q000378:metabolism*; D002540:Cerebral Cortex / Q000293:injuries / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D005911:Gliosis / Q000209:etiology / Q000378:metabolism* / Q000517:prevention & control*; D006624:Hippocampus / Q000293:injuries / Q000378:metabolism / Q000473:pathology; D053496:Inositol 1,4,5-Trisphosphate Receptors / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018696:Neuroprotective Agents / Q000378:metabolism; D058472:Receptors, Purinergic P2Y1 / Q000378:metabolism* / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology
chemical_list: D053496:Inositol 1,4,5-Trisphosphate Receptors; D018696:Neuroprotective Agents; D058472:Receptors, Purinergic P2Y1