Purinergic 2Y1 Receptor stimulation decreases cerebral edema and reactive gliosis in a Traumatic Brain Injury Model.

Oct 2012

Watts LT, Sprague S, Zheng W, Garling RJ, Jimenez D, Digicaylioglu M, Lechleiter JD.

Source

University of TExas Health Science Center at San Antonio, Department of Cellular and Structural Biology, 7703 Floyd Curl Drive, San Antonio, Texas, United States, 78229, 210-567-8186, 210-567-8152; wattsl@uthscsa.edu.

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 following injury do not currently exist. We recently reported that stimulation of the purinergic receptor subtype P2Y1R using 2-methylthioladenosine 5' diphosphate (2MeSADP) significantly reduced cytotoxic edema induced by photothrombosis (Zheng et al., 2010). Here, we tested whether P2Y1R stimulation was neuroprotective following 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 (AQ4) and glial fibrillary acidic protein (GFAP) 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) thirty minutes 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 IP3R2-/- mice treated with 2MeSADP. Immunocytochemical labeling of brain slices confirmed that P2Y1R expression was defined to cortical and hippocampal astrocytes, but not neurons. Taken together, the data show that stimulation of astrocytic P2Y1Rs significantly reduces brain injury following acute trauma and is mediated by the IP3-signaling pathway.

Mary Ann Liebert