title: Unconventional neuroprotection against Ca2+ -dependent insults by metalloporphyrin catalytic antioxidants.
abstract: We evaluated whether both inert and catalytically active metalloporphyrin antioxidants, meso-substituted with either phenyl-based or N-alkylpyridinium-based groups, suppress Ca(2+)-dependent neurotoxicity in cell culture models of relevance to cerebral ischemia. Representatives from both metalloporphyrin classes, regardless of antioxidant strength, protected cultured cortical neurons or PC-12 cultures against the Ca(2+) ionophores ionomycin or A23187, by suppressing neurotoxic Ca(2+) influx. Some metalloporphyrins suppressed excitotoxic Ca(2+) influx indirectly induced by the Ca(2+) ionophores in cortical neurons. Metalloporphyrins did not quench intracellular fluorescence, suggesting localization to the plasma membrane interface and/or interference with Ca(2+) ionophores. Metalloporphyrins suppressed ionomycin-induced Mn(2+) influx, but did not protect cortical neurons against pyrithione, a Zn(2+) ionophore. In other Ca(2+)-dependent paradigms, Ca(2+) influx via plasma membrane depolarization, but not through reversal of plasmalemmal Na(+)/Ca(2+) exchangers, was modestly suppressed by Mn(III)meso-tetrakis(4-benzoic acid)porphyrin (Mn(III)TBAP) or by an inert analog, Zn(II)TBAP. Mn(III)TBAP and Zn(II)TBAP potently protected cortical neurons against long-duration oxygen-glucose deprivation (OGD), performed in the presence of antagonists of NMDA, alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate and L-type voltage-gated Ca(2+) channels, raising the possibility of an unconventional mode of blockade of transient receptor protein melastatin 7 channels by a metalloTBAP family of metalloporphyrins. The present study extends the range of Ca(2+)-dependent insults for which metalloporphyrins demonstrate unconventional neuroprotection. MetalloTBAPs appear capable of targeting an OGD temporal continuum.
authors.affiliation: National Research Council, Institute for Biological Sciences, Synaptic Pathophysiology Group, Ottawa, Ontario, 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: Lech
authors.initials: L
authors.lastname: Kiedrowski
authors.forename: Karine
authors.initials: K
authors.lastname: Lortie
authors.forename: Melissa
authors.initials: M
authors.lastname: Hewitt
authors.forename: Paul
authors.initials: P
authors.lastname: Morley
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D002545:Brain Ischemia / Q000188:drug therapy / Q000473:pathology; D002118:Calcium / Q000378:metabolism; D020013:Calcium Signaling / Q000502:physiology*; D002384:Catalysis; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology / Q000187:drug effects; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology; D005452:Fluoresceins / Q000378:metabolism; D018698:Glutamic Acid / Q000378:metabolism; D008665:Metalloporphyrins / Q000378:metabolism*; D016202:N-Methylaspartate / Q000494:pharmacology; D009474:Neurons / Q000473:pathology; D018696:Neuroprotective Agents; D020258:Neurotoxicity Syndromes / Q000473:pathology; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism; D019831:Sodium-Calcium Exchanger / Q000378:metabolism; D050053:TRPM Cation Channels / Q000378:metabolism
chemical_list: D000975:Antioxidants; D018690:Excitatory Amino Acid Agonists; D005452:Fluoresceins; D008665:Metalloporphyrins; D018696:Neuroprotective Agents; D017382:Reactive Oxygen Species; D019831:Sodium-Calcium Exchanger; D050053:TRPM Cation Channels; C074530:potassium-dependent sodium-calcium exchanger; D018698:Glutamic Acid; D016202:N-Methylaspartate; C486584:Trpm7 protein, rat; D002118:Calcium; C007740:fluorexon