Research ReportEarly ghrelin treatment attenuates disruption of the blood brain barrier and apoptosis after traumatic brain injury through a UCP-2 mechanism

Ghrelin has been shown to be anti-inflammatory and neuroprotective in models of neurologic injury. We hypothesize that treatment with ghrelin will attenuate breakdown of the blood brain barrier (BBB) and apoptosis 24 h following traumatic brain injury (TBI). We believe this protection is at least in part mediated by up-regulation of UCP-2, thereby stabilizing mitochondria and preventing up-regulation of caspase-3. A weight drop model was used to create severe TBI. Balb/c mice were divided into 3 groups. Sham: no TBI or ghrelin treatment; TBI: TBI only; TBI/ghrelin: 20 μg (IP) ghrelin at the time of TBI. BBB permeability to 70 kDa FITC-Dextran was measured 24 h following injury and quantified in arbitrary integrated fluorescence (afu). Brain tissue was subjected to TUNEL staining and TUNEL positive cells were quantified. Immunohistochemistry was performed on injured tissue to reveal patterns of caspase-3 and UCP-2 expression. TBI increased cerebral vascular permeability by three-fold compared to sham. Ghrelin treatment restored vascular permeability to the level of shams. TUNEL staining showed that ghrelin mitigated the significant increase in apoptosis that follows TBI. TBI increased both caspase-3 compared to sham. Treatment with ghrelin significantly increased UCP-2 compared to TBI alone and this increase in UCP-2 expression was associated with a decrease in expression of caspase-3. Early ghrelin treatment prevents TBI induced BBB disruption and TBI mediated apoptosis 24 h following injury. These results demonstrate the neuroprotective potential of ghrelin as a therapy in TBI.

► Ghrelin improves post-TBI histologic changes. ► Ghrelin decreases traumatic brain injury (TBI) induced blood brain barrier (BBB) dysfunction. ► Ghrelin decreases neuronal apoptosis following TBI. ► Ghrelin administration after TBI is associated with increased UCP-2 and decreased Caspase-3. ► Ghrelin may provide a promising therapeutic approach for reducing secondary injury following TBI.