Superoxide dismutase/catalase mimetics but not MAP kinase inhibitors are neuroprotective against oxygen/glucose deprivation-induced neuronal death in hippocampus.
Although oxygen/glucose deprivation (OGD) has been widely used as a model of ischemic brain damage, the mechanisms underlying acute neuronal death in this model are not yet well understood. We used OGD in acute hippocampal slices to investigate the roles of reactive oxygen species and of the mitogen-activated protein kinases (MAPKs) in neuronal death. In particular, we tested the neuroprotective effects of two synthetic superoxide dismutase/catalase mimetics, EUK-189 and EUK-207. Acute hippocampal slices prepared from 2-month-old or postnatal day 10 rats were exposed to oxygen and glucose deprivation for 2 h followed by 2.5 h reoxygenation. Lactate dehydrogenase (LDH) release in the medium and propidium iodide (PI) uptake were used to evaluate cell viability. EUK-189 or EUK-207 applied during the OGD and reoxygenation periods decreased LDH release and PI uptake in slices from 2-month-old rats. EUK-189 or EUK-207 also partly blocked OGD-induced ATP depletion and extracellular signal-regulated kinases 1 and 2 (ERK1/2) dephosphorylation, and completely eliminated reactive oxygen species generation. The MEK inhibitor U0126 applied together with EUK-189 or EUK-207 completely blocked ERK1/2 activation, but had no effect on their protective effects against OGD-induced LDH release. U0126 alone had no effect on OGD-induced LDH release. EUK-207 had no effect on OGD-induced p38 or c-Jun N-terminal kinase dephosphorylation, and when the p38 inhibitor SB203580 was applied together with EUK-207, it had no effect on the protective effects of EUK-207. SB203580 alone had no effect on OGD-induced LDH release either. In slices from p10 rats, OGD also induced high-LDH release that was partly reversed by EUK-207; however, neither OGD nor EUK-207 produced significant changes in ERK1/2 and p38 phosphorylation. OGD-induced spectrin degradation was not modified by EUK-189 or EUK-207 in slices from p10 or 2-month-old rats, suggesting that their protective effects was not mediated through inhibition of calpain activation. Thus, both EUK-189 and EUK-207 provide neuroprotection in acute ischemic conditions, and this effect is related to elimination of free radical formation and partial reversal of ATP depletion, but not mediated by the activation or inhibition of the MEK/ERK or p38 pathways, or inhibition of calpain activation.
Zhou
Miou
M
Neuroscience Program, University of Southern California, Los Angeles, California, USA.
Dominguez
Reymundo
R
Baudry
Michel
M
D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D000831:Animals, Newborn; D002154:Calpain / Q000187:drug effects / Q000378:metabolism; D002374:Catalase / Q000378:metabolism*; D016923:Cell Death / Q000187:drug effects / Q000502:physiology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005609:Free Radicals / Q000378:metabolism; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism* / Q000503:physiopathology; D020925:Hypoxia-Ischemia, Brain / Q000378:metabolism* / Q000503:physiopathology; D007770:L-Lactate Dehydrogenase / Q000187:drug effects / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000502:physiology; D018716:Molecular Mimicry / Q000187:drug effects / Q000502:physiology; D018696:Neuroprotective Agents / Q000378:metabolism* / Q000494:pharmacology; D009924:Organ Culture Techniques; D009942:Organometallic Compounds / Q000494:pharmacology; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology; D010766:Phosphorylation / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D012459:Salicylates / Q000494:pharmacology; D013482:Superoxide Dismutase / Q000378:metabolism*; D000072105:Superoxide Dismutase-1
C476761:EUK 207; C436526:EUK-189; D004791:Enzyme Inhibitors; D005609:Free Radicals; D018696:Neuroprotective Agents; D009942:Organometallic Compounds; D012459:Salicylates; D000255:Adenosine Triphosphate; D007770:L-Lactate Dehydrogenase; D002374:Catalase; C000606292:Sod1 protein, rat; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1; D002154:Calpain