Oral administration of glutathione improves memory deficits following transient brain ischemia by reducing brain oxidative stress

Neuroscience. 2013 Oct 10:250:394-407. doi: 10.1016/j.neuroscience.2013.07.017. Epub 2013 Jul 18.


Oxidative stress aggravates brain injury following ischemia. The glutathione (GSH) system plays a pivotal role in combating oxidative stress in various cell types. To determine whether oral GSH administration elicits anti-oxidative effects, we assessed its potential neuroprotective effects in transient bilateral common carotid artery occlusion (BCCAO) mice. In naïve mice, acute oral administration of GSH significantly increased GSH levels by 1h in the cortex and hippocampus. Eleven days after BCCAO, untreated mice showed significantly decreased GSH levels and an inverse elevation of glutathione-disulfide (GSSG) levels in both the cortex and hippocampus. Oral administration of GSH (100 and 500 mg/kg p.o.) for 10 consecutive days after ischemia restored reduced GSH levels and inhibited GSSG elevation. Notably, post-administration of GSH (100 and 500 mg/kg p.o.) significantly prevented neuronal cell death in the hippocampal CA1 region in BCCAO mice, an effect closely correlated with decreased levels of oxidative markers such as 4-hydroxy-2-nonenal (4-HNE), 8-hydroxy-2-deoxyguanosine (8-OHdG) and nitrotyrosine in that region. Finally, GSH administration for 10 days improved memory deficits observed in BCCAO mice. Taken together, our findings indicate that the anti-oxidative effect of oral GSH administration ameliorates post-ischemia neuronal cell death and, in turn, may improve memory.

Keywords: 4-HNE; 4-hydroxy-2-nonenal; 8-OHdG; 8-hydroxy-2-deoxyguanosine; ANOVA; BCCAO; Ca(2+)/calmodulin-dependent protein kinase II; CaMKII; EDTA; GSH; GSSG; HSP70; LTP; MCAO; N-ethylmaleimide; NEM; NO; OPT; PBS; PI; ROS; SEM; SUMO1; TIA; TUNEL; analysis of variance; bilateral common carotid arteries occlusion; ethylenediaminetetraacetic acid; glutathione; glutathione-disulfide; heat-shock protein 70; long-term potentiation; middle cerebral artery occlusion; neuroprotection; nitric oxide; o-phthalaldehyde; oxidative stress; phosphate-buffered saline; propidium iodide; reactive oxygen species; small ubiquitin-like modifier 1; standard error of the mean; terminal deoxynucleotidyl transferase-mediated dUTP-nick-end-labeling; transient ischemic attack.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Avoidance Learning / drug effects
  • Blotting, Western
  • Brain / pathology
  • Brain Chemistry / drug effects
  • CA1 Region, Hippocampal / pathology
  • Cell Death / drug effects
  • DNA Fragmentation
  • Glutathione / administration & dosage
  • Glutathione / pharmacology*
  • Glutathione Disulfide / metabolism
  • Immunohistochemistry
  • In Situ Nick-End Labeling
  • Ischemic Attack, Transient / complications
  • Ischemic Attack, Transient / pathology
  • Ischemic Attack, Transient / psychology*
  • Male
  • Maze Learning
  • Memory Disorders / drug therapy*
  • Memory Disorders / etiology
  • Memory Disorders / psychology*
  • Mice
  • Mice, Inbred C57BL
  • Neuroprotective Agents*
  • Oxidative Stress / drug effects*
  • Psychomotor Performance / drug effects
  • Recognition, Psychology / drug effects


  • Neuroprotective Agents
  • Glutathione
  • Glutathione Disulfide