title: An alternative Ca2+-dependent mechanism of neuroprotection by the metalloporphyrin class of superoxide dismutase mimetics.
abstract: This study challenges the conventional view that metalloporphyrins protect cultured cortical neurons in models of cerebral ischemia by acting as intracellular catalytic antioxidants [superoxide dismutase (SOD) mimetics]. High SOD-active Mn(III)porphyrins meso-substituted with N,N'-dimethylimidazolium or N-alkylpyridinium groups did not protect neurons against oxygen-glucose deprivation (OGD), although lower SOD-active and -inactive para isomers protected against N-methyl-D-aspartate (NMDA) exposure. Mn(III)meso-tetrakis(4-benzoic acid)porphyrin (Mn(III)TBAP), as well as SOD-inactive metalloTBAPs and other phenyl ring- or beta-substituted metalloporphyrins that contained redox-insensitive metals, protected cultures against OGD and NMDA neurotoxicity. Crucially, neuroprotective metalloporphyrins suppressed OGD- or NMDA-induced rises in intracellular Ca2+ concentration in the same general rank order as observed for neuroprotection. Results from paraquat toxicity, intracellular fluorescence quenching, electrophysiology, mitochondrial Ca2+, and spontaneous synaptic activity experiments suggest a model in which metalloporphyrins, acting at the plasma membrane, protect neurons against OGD by suppressing postsynaptic NMDA receptor-mediated Ca2+ rises, thereby indirectly preventing accumulation of neurotoxic mitochondrial Ca2+ levels. Though neuroprotective in a manner not originally intended, SOD-inactive metalloporphyrins may represent promising therapeutic agents in diseases such as cerebral ischemia, in which Ca2+ toxicity is implicated. Conventional syntheses aimed at improving the catalytic antioxidant capability and/or intracellular access of metalloporphyrins may not yield improved efficacy in some disease models.
authors.affiliation: National Research Council, Institute for Biological Sciences, Synaptic Pathophysiology Group, Ottawa, ON, Canada. joe.tauskela@nrc-cnrc.gc.ca
authors.forename: Joseph S
authors.initials: JS
authors.lastname: Tauskela
authors.forename: Eric
authors.initials: E
authors.lastname: Brunette
authors.forename: Natasha
authors.initials: N
authors.lastname: O'Reilly
authors.forename: Geoff
authors.initials: G
authors.lastname: Mealing
authors.forename: Tanya
authors.initials: T
authors.lastname: Comas
authors.forename: Tania F
authors.initials: TF
authors.lastname: Gendron
authors.forename: Robert
authors.initials: R
authors.lastname: Monette
authors.forename: Paul
authors.initials: P
authors.lastname: Morley
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000378:metabolism; D002545:Brain Ischemia / Q000473:pathology; D002118:Calcium / Q000737:chemistry / Q000378:metabolism*; D002259:Carbonyl Cyanide p-Trifluoromethoxyphenylhydrazone / Q000494:pharmacology; D002384:Catalysis; D002462:Cell Membrane / Q000378:metabolism; D002478:Cells, Cultured; D018920:Coculture Techniques; D004594:Electrophysiology; D016166:Free Radical Scavengers / Q000494:pharmacology; D005947:Glucose / Q000378:metabolism; D007093:Imidazoles / Q000737:chemistry; D008665:Metalloporphyrins / Q000737:chemistry* / Q000494:pharmacology; D008928:Mitochondria / Q000378:metabolism; D008956:Models, Chemical; D016202:N-Methylaspartate / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D018696:Neuroprotective Agents / Q000494:pharmacology*; D010084:Oxidation-Reduction; D010100:Oxygen / Q000378:metabolism; D010269:Paraquat / Q000494:pharmacology; D010539:Permeability; D051381:Rats; D013482:Superoxide Dismutase / Q000737:chemistry* / Q000378:metabolism; D009435:Synaptic Transmission / Q000187:drug effects; D013997:Time Factors
chemical_list: D000975:Antioxidants; D016166:Free Radical Scavengers; D007093:Imidazoles; D008665:Metalloporphyrins; D018696:Neuroprotective Agents; C097284:manganese(III)-tetrakis(4-benzoic acid)porphyrin; D002259:Carbonyl Cyanide p-Trifluoromethoxyphenylhydrazone; D016202:N-Methylaspartate; D013482:Superoxide Dismutase; D005947:Glucose; D010269:Paraquat; D010100:Oxygen; D002118:Calcium