EUK-207, a superoxide dismutase/catalase mimetic, is neuroprotective against oxygen/glucose deprivation-induced neuronal death in cultured hippocampal slices.
EUK-207 is a synthetic superoxide dismutase/catalase mimetic that has been shown to reverse age-related learning deficits and brain oxidative stress in mice. In the present experiments, we tested the effects of EUK-207 on oxygen/glucose deprivation (OGD)-induced cell death in cultured hippocampal slices and on several mechanisms that have been postulated to participate in this process. Cultured hippocampal slices were subjected to 1 h OGD followed by 3 or 24 h recovery in regular medium with glucose and oxygen. Lactate dehydrogenase (LDH) release in culture medium and propidium iodide (PI) uptake in slices were used to evaluate cell viability. When EUK-207 was applied either 1 or 2 h before OGD, OGD-induced LDH release was significantly reduced. When EUK-207 was applied 1 h before OGD and during 24 h recovery, PI uptake was also reduced. OGD-induced accumulation of reactive oxygen species (ROS) was evaluated with the fluorescent probe DCF. DCF fluorescence in slices increased steadily during OGD treatment, rapidly disappeared following return to regular medium before slowly increasing again during the 24 h recovery period. When measured 3 h after OGD, increased ROS levels were significantly reduced by EUK-207. OGD also increased lipid peroxidation levels and this effect was also reduced by EUK-207 6 h following OGD. Cytosolic cytochrome c and nuclear apoptosis-inducing factor (AIF) were increased 3 h after OGD, and the translocation of AIF from mitochondria to nucleus was partly blocked by treatment with EUK-207. In conclusion, EUK-207 provides neuroprotection against OGD-induced cell death in cultured hippocampal slices. As EUK-207 prevents free radical formation and lipid peroxidation, the neuroprotection is related to elimination of free radical generation and lipid peroxidation, as well as to decreased activation of pro-apoptotic factors. Our data support the further clinical evaluation of this class of molecules for the prevention of ischemic cell damage.
Zhou
Miou
M
Neuroscience Program, HNB534, University of Southern California, Los Angeles, CA 90089-2520, USA.
Baudry
Michel
M
D000818:Animals; D051033:Apoptosis Inducing Factor / Q000187:drug effects / Q000378:metabolism; D002374:Catalase / Q000187:drug effects / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects / Q000502:physiology; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D045304:Cytochromes c / Q000378:metabolism; D005456:Fluorescent Dyes; D016166:Free Radical Scavengers / Q000494:pharmacology / Q000627:therapeutic use; D006624:Hippocampus / Q000187:drug effects / Q000201:enzymology / Q000503:physiopathology; D020925:Hypoxia-Ischemia, Brain / Q000188:drug therapy* / Q000201:enzymology / Q000503:physiopathology; D007770:L-Lactate Dehydrogenase / Q000187:drug effects / Q000378:metabolism; D015227:Lipid Peroxidation / Q000187:drug effects / Q000502:physiology; D009410:Nerve Degeneration / Q000188:drug therapy* / Q000201:enzymology / Q000209:etiology; D009474:Neurons / Q000187:drug effects* / Q000201:enzymology; D018696:Neuroprotective Agents / Q000494:pharmacology / Q000627:therapeutic use; D009924:Organ Culture Techniques; D009942:Organometallic Compounds / Q000494:pharmacology* / Q000627:therapeutic use; D018384:Oxidative Stress / Q000187:drug effects* / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000037:antagonists & inhibitors / Q000378:metabolism; D013482:Superoxide Dismutase / Q000187:drug effects* / Q000378:metabolism
D051033:Apoptosis Inducing Factor; C476761:EUK 207; D005456:Fluorescent Dyes; D016166:Free Radical Scavengers; D018696:Neuroprotective Agents; D009942:Organometallic Compounds; D017382:Reactive Oxygen Species; D045304:Cytochromes c; D007770:L-Lactate Dehydrogenase; D002374:Catalase; D013482:Superoxide Dismutase