title: Tin protoporphyrin provides protection following cerebral hypoxia-ischemia: involvement of alternative pathways.
abstract: The contribution of heme oxygenase (HO)-linked pathways to neurodegeneration following cerebral hypoxia-ischemia (HI) remains unclear. We investigated whether HO modulators affected HI-induced brain damage and explored potential mechanisms involved. HI was induced in 26-day-old male Wistar rats by left common carotid artery ligation, followed by exposure to a humidified atmosphere of 8% oxygen for 1 hr. Tin protoporphyrin (SnPP; an HO inhibitor), ferriprotoporphyrin (FePP; an HO inducer), or saline was administered intraperitoneally once daily from 1 day prior to HI until sacrifice at 3 days post-HI. SnPP reduced (P < 0.05) infarct volume compared with saline-treated animals, but FePP had no effect on brain injury. SnPP did not significantly inhibit HO activity at 3 days post-HI, but SnPP increased (P < 0.001) total nitric oxide synthase (NOS) activity compared with HI + saline. Both inducible NOS and cyclooxygenase activities were attenuated (P < 0.05) by SnPP, whereas mitochondrial complex I and V activities were augmented (P < 0.05) by SnPP. SnPP had no effect on NMDA receptor currents. Overall, like other HO inhibitors, SnPP produced many nonselective effects, such as attenuation of inflammatory enzymes and increased mitochondrial respiratory function, which were associated with a protective response 3 days post-HI.
authors.affiliation: Department of Pharmacology and Toxicology, University of Otago, Dunedin, New Zealand. brad.sutherland@ndm.ox.ac.uk
authors.forename: Brad A
authors.initials: BA
authors.lastname: Sutherland
authors.forename: Odette M
authors.initials: OM
authors.lastname: Shaw
authors.forename: Andrew N
authors.initials: AN
authors.lastname: Clarkson
authors.forename: Ian C
authors.initials: IC
authors.lastname: Winburn
authors.forename: Adam C
authors.initials: AC
authors.lastname: Errington
authors.forename: Christine L
authors.initials: CL
authors.lastname: Dixon
authors.forename: George
authors.initials: G
authors.lastname: Lees
authors.forename: Ivan A
authors.initials: IA
authors.lastname: Sammut
authors.forename: Ian
authors.initials: I
authors.lastname: Appleton
mesh_terms: D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D042967:Electron Transport Complex I / Q000378:metabolism; D003576:Electron Transport Complex IV / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006419:Heme Oxygenase (Decyclizing) / Q000037:antagonists & inhibitors*; D006427:Hemin / Q000494:pharmacology*; D020925:Hypoxia-Ischemia, Brain / Q000378:metabolism*; D008297:Male; D008665:Metalloporphyrins / Q000494:pharmacology*; D019001:Nitric Oxide Synthase / Q000378:metabolism; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism; D011524:Protoporphyrins / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar
chemical_list: D004791:Enzyme Inhibitors; D008665:Metalloporphyrins; D011524:Protoporphyrins; D006427:Hemin; C032628:tin protoporphyrin IX; D019001:Nitric Oxide Synthase; D006419:Heme Oxygenase (Decyclizing); D011451:Prostaglandin-Endoperoxide Synthases; D003576:Electron Transport Complex IV; D042967:Electron Transport Complex I