An alternative Ca2+-dependent mechanism of neuroprotection by the metalloporphyrin class of superoxide dismutase mimetics.
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.
Tauskela
Joseph S
JS
National Research Council, Institute for Biological Sciences, Synaptic Pathophysiology Group, Ottawa, ON, Canada. joe.tauskela@nrc-cnrc.gc.ca
Brunette
Eric
E
O'Reilly
Natasha
N
Mealing
Geoff
G
Comas
Tanya
T
Gendron
Tania F
TF
Monette
Robert
R
Morley
Paul
P
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
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