Competing approaches to excitotoxic neuroprotection by inert and catalytic antioxidant porphyrins

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.