The cytosolic redox status modulates ion channels and receptors by oxidizing/reducing their sulfhydryl (SH) groups. We therefore analyzed to what degree SH-modulation affects hippocampal susceptibility to hypoxia. In rat hippocampal slices, severe hypoxia caused a massive depolarization of CA1 neurons and a negative shift of the extracellular DC potential, the characteristic sign of hypoxia-induced spreading depression (HSD). Oxidizing SH groups by DTNB (5,5-dithiobis 2-nitrobenzoic acid, 2 mM) postponed HSD by 30%, while their reduction by DTT (1,4-dithio-DL-threitol, 2 mM) or alkylation by NEM (N-ethylmaleimide, 500 µM) hastened HSD onset. The DTNB-induced postponement of HSD was not affected by tolbutamide (200 µM), DL-AP5 (150 µM) or CNQX (25 µM). It was abolished, however, by Ni²⁺ (2 mM), withdrawal of extracellular Ca²⁺, charybdotoxin (25 nM), and iberiotoxin (50 nM). In CA1 neurons DTNB induced a moderate hyperpolarization, blocked spontaneous spike discharges and postponed the massive hypoxic depolarization. DTT induced burst firing, depolarized glial cells, and hastened the onset of the massive hypoxic depolarization. Schaffer-collateral/CA1 synapses were blocked by DTT but not by DTNB; axonal conduction remained intact. Mitochondria did not markedly respond to DTNB or DTT. While the targets of DTT are less clear, the postponement of HSD by DTNB indicates that sulfhydryl oxidation increases the tolerance of hippocampal tissue slices against hypoxia. As underlying mechanism we identified the activation of BK channels in a Ca²⁺ -sensitive manner. Accordingly, ionic disregulation and the loss of membrane potential occur later or might even be prevented during short-term insults. Therefore, well directed oxidation of SH-groups could mediate neuroprotection.