Sulfhydryl oxidation: a potential strategy to achieve neuroprotection during severe hypoxia?

Abstract

Previously we reported that sulfhydryl (SH) modulation affects the susceptibility of rat hippocampal slices to severe hypoxia. SH-oxidation by DTNB (5,5'-dithiobis 2-nitrobenzoic acid) or H2O2 postponed the onset of hypoxia-induced spreading depression (HSD), thereby delaying the loss of neuronal function, whereas SH-reduction by DTT (1,4-dithio-dl-threitol) hastened HSD onset. To judge the neuroprotective merit that might arise from a postponement of HSD by oxidants, we have extended our earlier observations by multiparametric recordings and screened for changes in the extracellular K+ accumulation, HSD propagation velocity, and its maximum spread. As parameters for neuronal network function, the failure of synapses during hypoxia and their posthypoxic recovery were analyzed. DTNB (2 mM) or H2O2 (5 mM) postponed HSD but did not attenuate the rise in extracellular K+ concentration ([K+](o)), HSD propagation velocity or its maximum spread. H2O2 slightly postponed the synaptic failure during hypoxia; the posthypoxic recovery of synapses was, however, incomplete. DTNB slowed the synaptic recovery upon reoxygenation. DTT (2 mM) hastened HSD onset, but HSD propagation velocity and tissue invasion were not affected. Upon reoxygenation, however, normalization of [K+](o) was disturbed and synaptic recovery failed. Therefore, SH-reducing conditions at the onset of HSD proved to be devastating for the hippocampal network. In conclusion, the only merit of DTNB or H2O2 treatment is a delayed HSD onset, i.e. some extra time before neuronal function is lost during severe hypoxia. Attenuation of the severe changes during HSD or an improved outcome was not observed. Nevertheless, combination of SH-oxidants with established neuroprotectants might be a potential therapeutic approach.

• Authors: S Hepp, M Müller
• Journal: Neuroscience (Neuroscience) Vol. 152 Issue 4 Pg. 903-12 (Apr 09 2008) ISSN: 0306-4522 [Print] United States
• PMID: 18343593 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Neuroprotective Agents
• Sulfhydryl Reagents
• Dithioerythritol
• Dithionitrobenzoic Acid
• Hydrogen Peroxide
• Potassium

Topics

• Animals
• Cortical Spreading Depression (drug effects, radiation effects)
• Dithioerythritol (pharmacology)
• Dithionitrobenzoic Acid (pharmacology)
• Electric Stimulation
• Evoked Potentials (drug effects, radiation effects)
• Hippocampus (drug effects, physiopathology)
• Hydrogen Peroxide (pharmacology)
• Hypoxia (pathology, prevention & control)
• In Vitro Techniques
• Male
• Neuroprotective Agents (therapeutic use)
• Oxidation-Reduction (drug effects)
• Potassium (metabolism)
• Rats
• Rats, Sprague-Dawley
• Sulfhydryl Reagents (pharmacology)