title: Competing approaches to excitotoxic neuroprotection by inert and catalytic antioxidant porphyrins.
abstract: The goal of this study was to determine if novel porphyrins protect cultured cortical neurons from excitotoxic NMDA exposure or oxygen-glucose deprivation (OGD), which model key aspects of cerebral ischemia. Porphyrins were chosen based on conventional and unconventional criteria. Metalloporphyrin catalytic antioxidants possessing a redox-sensitive metal core can exhibit potent and wide-ranging catalytic antioxidant abilities, which are conventionally believed to underlie neuroprotection. We report here that a recent-generation potent peroxynitrite decomposition catalyst, FP-15, protected a majority of neurons against OGD and NMDA toxicity, without suppressing NMDA-mediated intracellular Ca2+ (Cai2+) elevations or whole-cell currents. We have previously shown that neuroprotection against OGD and NMDA toxicity correlated with an ability to suppress neurotoxic Cai2+ elevations and not antioxidant ability. We now evaluate if this unconventional mechanism extends to inert metal-free porphyrins. Neuron cultures were completely protected against OGD and NMDA toxicity by H2-meso-tetrakis(3-benzoic acid)porphyrin (H2-TBAP(3)) or H2-meso-tetrakis(4-sulfonatophenyl)porphyrin (H2-TPPS(4)), although only H2-TPPS(4) suppressed (completely) NMDA-induced Cai2+ rises. H2-meso-tetrakis(3,3'-benzoic acid)porphyrin (H2-TBAP(3,3')) or H2-meso-tetrakis(N-methylpyridynium-4-yl)porphyrin (H2-TM-PyP(4)) provided at least partial protection against OGD and NMDA toxicity and partially suppressed NMDA-induced Cai2+ elevations. Despite the complexity of Ca2+-independent and -dependent based mechanisms, the inventory of porphyrins demonstrating neuroprotection in ischemia-relevant insults is now expanded to include FP-15 and inert metal-free compounds, although with no apparent advantage gained by using FP-15.
authors.affiliation: National Research Council, Institute for Biological Sciences, Synaptic Pathophysiology Group, Montreal Road Campus, Building M-54, Ottawa, Ontario, Canada K1A 0R6. joe.tauskela@nrc-cnrc.gc.ca
authors.forename: Joseph Stephen
authors.initials: JS
authors.lastname: Tauskela
authors.forename: Eric
authors.initials: E
authors.lastname: Brunette
authors.forename: Melissa
authors.initials: M
authors.lastname: Hewitt
authors.forename: Geoff
authors.initials: G
authors.lastname: Mealing
authors.forename: Paul
authors.initials: P
authors.lastname: Morley
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology; D004305:Dose-Response Relationship, Drug; D004622:Embryo, Mammalian; D018690:Excitatory Amino Acid Agonists / Q000633:toxicity*; D005947:Glucose / Q000172:deficiency; D000860:Hypoxia; D008665:Metalloporphyrins / Q000737:chemistry / Q000494:pharmacology*; D016202:N-Methylaspartate / Q000633:toxicity*; D009474:Neurons / Q000187:drug effects*; D018696:Neuroprotective Agents / Q000737:chemistry / Q000494:pharmacology*; D010716:Phosphatidylinositols / Q000378:metabolism; D051381:Rats
chemical_list: D018690:Excitatory Amino Acid Agonists; D008665:Metalloporphyrins; D018696:Neuroprotective Agents; D010716:Phosphatidylinositols; D016202:N-Methylaspartate; D005947:Glucose; D002118:Calcium