title: 17β-estradiol inhibits MMP-9 and SUR1/TrpM4 expression and activation and thereby attenuates BSCB disruption/hemorrhage after spinal cord injury in male rats.
abstract: Blood-spinal cord barrier (BSCB) disruption and progressive hemorrhage after spinal cord injury (SCI) lead to secondary injury and the subsequent apoptosis and/or necrosis of neuron and glia, causing permanent neurological deficits. In this study, we examined the effect of 17β-estradiol (E2) on BSCB breakdown and hemorrhage as well as subsequent inflammation after SCI. After a moderate contusion injury at the 9th thoracic segment of spinal cord, E2 (300 μg/kg) was administered by iv injection immediately after SCI, and the same dose of E2 was then administered 6 and 24 hours after injury. Our data show that E2 attenuated BSCB permeability and hemorrhage and reduced the infiltration of neutrophils and macorphages after SCI. Consistent with this finding, the expression of inflammatory mediators was significantly reduced by E2. Furthermore, E2 treatment significantly inhibited the expression of sulfonylurea receptor 1 and transient receptor potential melastatin 4 after injury, which are known to mediate hemorrhage at an early stage after SCI. Moreover, the expression and activation of matrix metalloprotease-9 after injury, which is known to disrupt BSCB, and the degradation of tight junction proteins, such as zona occludens-1 and occludin, were significantly inhibited by E2 treatment. Furthermore, the protective effects of E2 on BSCB disruption and functional improvement were abolished by an estrogen receptor antagonist, ICI 182780 (3 mg/kg). Thus, our study provides evidence that the neuroprotective effect of E2 after SCI is, in part, mediated by inhibiting BSCB disruption and hemorrhage through the down-regulation of sulfonylurea receptor 1/transient receptor potential melastatin 4 and matrix metalloprotease-9, which is dependent on estrogen receptor.
authors.affiliation: Age-Related and Brain Diseases Research Center (J.Y.L., H.Y.C., T.Y.Y.) and Department of Biochemistry and Molecular Biology (T.Y.Y.), School of Medicine, Kyung Hee University, Seoul, 130-701, Korea; and Department of Life Science (W.H.N., B.G.J.), Sogang University, Seoul 121-742, Korea.
authors.forename: Jee Y
authors.initials: JY
authors.lastname: Lee
authors.forename: Hae Y
authors.initials: HY
authors.lastname: Choi
authors.forename: Won H
authors.initials: WH
authors.lastname: Na
authors.forename: Bong G
authors.initials: BG
authors.lastname: Ju
authors.forename: Tae Y
authors.initials: TY
authors.lastname: Yune
mesh_terms: D000818:Animals; D017209:Apoptosis; D001812:Blood-Brain Barrier / Q000187:drug effects* / Q000378:metabolism; D002199:Capillary Permeability / Q000187:drug effects*; D015536:Down-Regulation / Q000187:drug effects; D004958:Estradiol / Q000031:analogs & derivatives / Q000494:pharmacology*; D065171:Estrogen Receptor Antagonists / Q000494:pharmacology; D000077267:Fulvestrant; D006470:Hemorrhage / Q000378:metabolism*; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000187:drug effects* / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013119:Spinal Cord Injuries / Q000378:metabolism*; D064233:Sulfonylurea Receptors / Q000187:drug effects* / Q000378:metabolism; D050053:TRPM Cation Channels / Q000187:drug effects* / Q000378:metabolism
chemical_list: C577509:Abcc8 protein, rat; D065171:Estrogen Receptor Antagonists; D064233:Sulfonylurea Receptors; D050053:TRPM Cation Channels; C500239:TRPM4 protein, rat; D000077267:Fulvestrant; D004958:Estradiol; D020780:Matrix Metalloproteinase 9; C572337:Mmp9 protein, rat