Ghrelin inhibits BSCB disruption/hemorrhage by attenuating MMP-9 and SUR1/TrpM4 expression and activation after spinal cord injury

• Published in: Biochimica et biophysica acta Vol. 1842; no. 12; pp. 2403 - 2412
• Main Authors: Lee, Jee Y., Choi, Hae Y., Na, Won H., Ju, Bong G., Yune, Tae Y.
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.12.2014
• Subjects: Animals; Blood spinal cord barrier; Blotting, Western; Capillary Permeability - drug effects; Gene Expression - drug effects; Ghrelin; Ghrelin - administration & dosage; Ghrelin - pharmacology; Hemorrhage; Hemorrhage - prevention & control; Immunohistochemistry; Inflammation Mediators - metabolism; Injections, Intraperitoneal; Macrophages - drug effects; Macrophages - metabolism; Male; Matrix metalloprotease; Matrix Metalloproteinase 9 - genetics; Matrix Metalloproteinase 9 - metabolism; Neutrophils - drug effects; Neutrophils - metabolism; Oligopeptides - pharmacology; Rats, Sprague-Dawley; Receptors, Ghrelin - antagonists & inhibitors; Receptors, Ghrelin - metabolism; Reverse Transcriptase Polymerase Chain Reaction; Spinal Cord - blood supply; Spinal Cord - drug effects; Spinal Cord Injuries - genetics; Spinal Cord Injuries - metabolism; Spinal Cord Injuries - physiopathology; Sulfonylurea receptor 1; Sulfonylurea Receptors - genetics; Sulfonylurea Receptors - metabolism; Time Factors; Transient receptor potential melastatin 4; TRPM Cation Channels - genetics; TRPM Cation Channels - metabolism; BBB; IL; COX-2; SUR1; VPA; Ghrelin receptor; Sulfonylurea receptor 1; i.p; Transient receptor potential melastatin 4; TrpM4; TNF; Hemorrhage; BSCB; MMP; Ghrelin; TJ; Blood spinal cord barrier; SCI; iNOS; Matrix metalloprotease
• ISSN: 0925-4439; 0006-3002; 1879-260X; 1878-2434
• DOI: 10.1016/j.bbadis.2014.09.006

Blood spinal cord barrier (BSCB) disruption after spinal cord injury (SCI) leads to secondary injury and results in apoptosis of neurons and glia, leading to permanent neurological deficits. Here, we examined the effect of ghrelin on BSCB breakdown and hemorrhage after SCI. After moderate weight-drop contusion injury at T9 spinal cord, ghrelin (80μg/kg) was administered via intraperitoneal injection immediately after SCI and then the same dose of ghrelin was treated every 6h for 1d. Our data showed that ghrelin treatment significantly inhibited the expression and activation of matrix metalloprotease-9 (MMP-9) at 1d after SCI. The increases of sulfonylurea receptor 1 (SUR1) and transient receptor potential melastatin 4 (TrpM4) expressions at 1h and 8h after SCI respectively were also alleviated by ghrelin treatment. In addition, both BSCB breakdown and hemorrhage at 1d after injury were significantly attenuated by ghrelin. In parallel, the infiltration of blood cells such as neutrophils and macrophages was inhibited by ghrelin treatment at 1d and 5d after SCI respectively. We also found that ghrelin receptor, growth hormone secretagogue receptor-1a (GHS-R1a), was expressed in the blood vessel of normal spinal tissue. Furthermore, the inhibitory effects of ghrelin on hemorrhage and BSCB disruption at 1d after SCI were blocked by GHS-R1a antagonist, [D-Lys-3]-GHRP-6 (3mg/kg). Thus, these results indicate that the neuroprotective effect by ghrelin after SCI is mediated in part by blocking BSCB disruption and hemorrhage through the down-regulation of SUR1/TrpM4 and MMP-9, which is dependent on GHS-R1a. •Ghrelin inhibits MMP-9 expression and activation, thereby reducing BSCB permeability.•Ghrelin inhibits SUR1 and TrpM4 expression, thereby attenuating hemorrhage after SCI.•Ghrelin inhibits blood cells infiltration, thereby alleviating inflammation after SCI.•The effect of ghrelin on BSCB disruption and hemorrhage is mediated via GHS-R1a.