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An alternative Ca 2+ ‐dependent mechanism of neuroprotection by the metalloporphyrin class of superoxide dismutase mimetics
Author(s) -
Tauskela Joseph S.,
Brunette Eric,
O'Reilly Natasha,
Mealing Geoff,
Comas Tanya,
Gendron Tania F.,
Monette Robert,
Morley Paul
Publication year - 2005
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.05-3795fje
Subject(s) - neuroprotection , superoxide dismutase , nmda receptor , chemistry , neurotoxicity , intracellular , pharmacology , antioxidant , reactive oxygen species , biochemistry , biophysics , excitotoxicity , toxicity , biology , receptor , organic chemistry
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 β‐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 Ca 2+ concentration in the same general rank order as observed for neuroprotection. Results from paraquat toxicity, intracellular fluorescence quenching, electrophysiology, mitochondrial Ca 2+ , 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 Ca 2+ rises, thereby indirectly preventing accumulation of neurotoxic mitochondrial Ca 2+ 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 Ca 2+ 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.