Reactive oxygen species (ROS) are key players in ischemia-induced neurodegeneration. We investigated whether hippocampal neurons may lack sufficient redox-buffering capacity to protect against ROS attacks. Using organotypic hippocampal slice cultures (OHSCs) transiently exposed to oxygen and glucose deprivation (OGD) and gerbils suffering from a two-vessel occlusion (2VO) as complementary ex vivo and in vivo models, we have elucidated whether the intrinsic redox systems interfere with ischemia-induced neurodegeneration. Cell- type-specific immunohistological staining of hippocampal slice cultures revealed that pyramidal neurons, in contrast to astrocytes and microglia, express free thiols only weakly. In addition, free thiol levels were extensively decreased throughout the hippocampal formation immediately after OGD, but recovered within 24 hr after reperfusion. In parallel, progressive glia activation and proliferation were observed. Increased neuronal exposure to ROS was monitored by dihydroethidium oxidation in hippocampal pyramidal cell layers immediately after OGD. Coadministration of reduction equivalents (α-lipoic acid) and thiol-stimulating agents (enalapril, ambroxol) decreased ischemia-induced neuronal damage in OGD-treated OHSCs and in gerbils exposed to 2VO, whereas single drug applications remained ineffective. In summary, limited redox buffering capacities of pyramidal neurons may underlie their exceptional vulnerability to cerebral ischemia. Consistently, multidrug treatments supporting endogenous redox systems may offer a strategy to promote valid neuroprotection. © 2011 Wiley Periodicals, Inc.