Glyburide - Novel Prophylaxis and Effective Treatment for Traumatic Brain Injury.

摘要

Addressing specific objectives of the project we developed, constructed and implemented a cranium only blast injury apparatus (COBIA) for production of standardized and reliable rat model of dose dependent blast-TBI (bTBI) to study the direct transcranial effects of blast on the brain, independent of indirect transthoracic effects Detailed anatomical evaluation revealed that cranium only blast impacts brain-blood barrier transiently, immediately after the blast. Long term impact of the blast is manifested predominantly in the brain tissues at the density boundaries, with elevated markers of the neuroinflammation, neurodegeneration and neuronal cell death. COBIA bTBI resulted in the transient vestibulomotor abnormalities and long term spatial memory deficits. After COBIA bTBI Sur1 and TRPM4 RNA and protein up- regulation was detected as early 4 hours after the blast consistent with de- novo expression of the SUR1 regulated NCCa-ATP channel Studies (including GLP- compliant protocol) with chronic administration of the SUR1 antagonist showed that post-bTBI Glyburide does not alter blast-induced long term cognitive deficits but improves anxiety-like behavior. In contrast prophylactic treatment with Glyburide improved performance in spatial memory task related to the hippocampal function. Study on the human volunteers showed that Glyburide is safe drug to be used for potential prophylaxis against blast TBI.