Neuroprotection against staurosporine by metalloporphyrins independent of antioxidant capability.
Metalloporphyrin catalytic antioxidants are remarkably useful in protecting cells and tissues in a wide array of disease models, attributed primarily to functioning as superoxide dismutase (SOD) mimetics or by scavenging other reactive oxygen species (ROS). However, we recently showed that neuroprotection against Ca(2+)-dependent excitotoxic insults did not correlate with antioxidant strength or capability [25], raising the question of whether scavenging of ROS underlies neuroprotection in other types of neuronal injury. The protein kinase inhibitor staurosporine causes neuronal demise primarily by apoptosis. Neuroprotection from staurosporine by a limited number of metalloporphyrin antioxidants has previously been attributed to antioxidant action. In the current study, a wide array of anionic and cationic metalloporphyrins and porphyrins, ranging in antioxidant strength or capability, provided protection against staurosporine in cortical neuron and cerebellar granule neuron (CGN) culture. Neuroprotection did not correlate with antioxidant strength or capability. In CGN but not cortical neuron cultures, NMDA receptor antagonists also prevented neurotoxicity, so metalloporphyrins may also target this secondary mode of death induced by staurosporine. Neuroprotection observed with antioxidant-inactive controls raises the possibility of an additional, or perhaps alternative, mechanism by antioxidant analogs not involving ROS scavenging.
Tauskela
Joseph S
JS
National Research Council, Institute for Biological Sciences, Synaptic Therapies & Devices Group, Montreal Rd. Campus, Ottawa, ON, Canada K1A 0R6. joe.tauskela@nrc-cnrc.gc.ca
Brunette
Eric
E
D000818:Animals; D000975:Antioxidants / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D053148:Caspase 3 / Q000378:metabolism; D002478:Cells, Cultured; D002531:Cerebellum / Q000166:cytology; D002540:Cerebral Cortex / Q000166:cytology; D008665:Metalloporphyrins / Q000737:chemistry / Q000494:pharmacology*; D051379:Mice; D009474:Neurons / Q000166:cytology / Q000187:drug effects; D018696:Neuroprotective Agents / Q000494:pharmacology*; D047428:Protein Kinase Inhibitors / Q000633:toxicity*; D051381:Rats; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors; D019311:Staurosporine / Q000633:toxicity*; D013329:Structure-Activity Relationship
D000975:Antioxidants; D008665:Metalloporphyrins; D018696:Neuroprotective Agents; D047428:Protein Kinase Inhibitors; D016194:Receptors, N-Methyl-D-Aspartate; D053148:Caspase 3; D019311:Staurosporine