title: Inhibition of MMP-9 activity following hypoxic ischemia in the developing brain using a highly specific inhibitor.
abstract: Perinatal hypoxic ischemic (HI) brain injury is a leading cause of long-term neurological handicap in newborn babies. Recently, excessive activity of matrix metalloproteinases (MMPs), and in particular MMP-9, has been implicated in the aetiology of HI injuries to the immature brain. Our previous study suggested that MMP-9 may be involved in the development of the delayed injury processes following HI injury to the developing brain. Given this, we therefore propose that MMP-9 may be a useful target for rescue therapies in the injured developing brain. To address this, we chose to use SB-3CT, a highly selective inhibitor that is known to target only MMP-2 and MMP-9, to attenuate the elevated MMP-9 activity seen following HI injury to the developing brain. Twenty-one-day-old postnatal Wistar rats were subjected to unilateral carotid artery occlusion followed by exposure to hypoxia (8% oxygen for 1 h). SB-3CT (50 mg/kg body weight in 25% dimethyl sulphoxide/75% polyethylene glycol) or an equal volume of vehicle or saline diluent was then administered intraperitoneally at 2, 5 and 14 h following the insult. Gelatin zymography revealed that pro-MMP-9 levels were significantly reduced at 6 h following hypoxic ischaemia (p ≤ 0.05). However, our results showed that despite significantly inhibiting brain pro-MMP-9 activity after hypoxic ischaemia, SB-3CT failed to confer significant neuroprotection in postnatal day 21 rats 3 days after an HI insult. Further investigations are warranted using a recently reported selective water-soluble version of SB-3CT or another MMP-9 selective inhibitor to resolve the role of MMP-9 in the aetiology of HI injury in the developing brain.
authors.affiliation: The Liggins Institute, University of Auckland, Auckland, New Zealand.
authors.forename: Himani S
authors.initials: HS
authors.lastname: Ranasinghe
authors.forename: Arjan
authors.initials: A
authors.lastname: Scheepens
authors.forename: Ernest
authors.initials: E
authors.lastname: Sirimanne
authors.forename: Murray D
authors.initials: MD
authors.lastname: Mitchell
authors.forename: Christopher E
authors.initials: CE
authors.lastname: Williams
authors.forename: Mhoyra
authors.initials: M
authors.lastname: Fraser
mesh_terms: D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D001835:Body Weight / Q000187:drug effects; D001921:Brain / Q000254:growth & development*; D002544:Cerebral Infarction / Q000188:drug therapy / Q000201:enzymology; D002851:Chromatography, High Pressure Liquid; D004791:Enzyme Inhibitors / Q000493:pharmacokinetics / Q000494:pharmacology*; D006573:Heterocyclic Compounds, 1-Ring / Q000493:pharmacokinetics / Q000494:pharmacology*; D020925:Hypoxia-Ischemia, Brain / Q000150:complications / Q000201:enzymology*; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000187:drug effects*; D009419:Nerve Tissue Proteins / Q000096:biosynthesis; D009422:Nervous System Diseases / Q000209:etiology / Q000517:prevention & control; D051381:Rats; D017208:Rats, Wistar; D013450:Sulfones / Q000493:pharmacokinetics / Q000494:pharmacology*; D053719:Tandem Mass Spectrometry
chemical_list: D004791:Enzyme Inhibitors; D006573:Heterocyclic Compounds, 1-Ring; D009419:Nerve Tissue Proteins; C429533:SB 3CT compound; D013450:Sulfones; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9