The Hormone Ghrelin Prevents Disruption Of The Blood Brain Barrier Following Traumatic Brain Injury

Abstract

Introduction: Traumatic brain injury (TBI) remains a leading cause of death and disability in the United States. Significant effort has been focused on reducing neuronal damage from post-TBI inflammation and blood brain barrier (BBB) mediated edema. The orexigenic hormone, ghrelin, decreases inflammation in sepsis models and has recently been shown to be neuroprotective following subarachnoid hemorrhage. We hypothesize that ghrelin prevents cerebral vascular permeability and breakdown of the BBB following TBI. Methods: A weight drop model was used to create severe TBI in Balb/c mice in the right parietal lobe. Animals were divided into 3 groups. Group TBI: TBI only; Group TBI/ghrelin: animals were treated with 10 μg of intraperitoneal ghrelin immediately prior to and 10 minutes following TBI; Group Sham: opening of the skull but no TBI, nor ghrelin treatment. Brain vascular permeability to injected 70kDa FITC-Dextran was determined 6 hours following injury using an IVIS spectrum measuring radiated fluorescence. Extracted brain tissue was also used to measure expression of S100B, a marker of BBB disruption, by Western blot. Results: Six hours following injury, TBI increased cerebral vascular permeability to FITC-Dextran by two-fold as measured by radiated fluorescence(4.9±2.8 vs. 2.5 ±1.0 [p/s/cm2/sr] / [μW/cm2]). Ghrelin treated animals restored vascular permeability to that of sham levels (2.5±1.2 [p/s/cm2/sr] / [μW/cm2]). The corresponding figure shows representative coronal brain imaging, higher color intensity is indicative of increased permeability. Similarly, expression of S100B was increased by 4 fold in TBI animals compared to sham. Again, ghrelin treated animals decreased post-TBI expression of S100B to that of sham. Conclusion: In a mouse model of TBI, ghrelin prevented post-TBI BBB disruption as measured by cerebral vascular permeability and S100B. These preliminary results demonstrate potential neuroprotective effects of ghrelin which could be developed as a future therapeutic agent in TBI.