H2-Induced Nrf2 Activation Ameliorates Cerebral Ischemia-Reperfusion InjuryScientific Research

Abstract:

Molecular hydrogen has been proved effective in ameliorating cerebral ischemia/reperfusion (I/R) injury by selectively neutralizing reactive oxygen species. Lactulose can produce considerable amount of hydrogen through fermentation by the bacteria in the gastrointestinal tract. To determine the neuroprotective effects of lactulose against cerebral I/R injury in rats and explore the probable mechanisms, we carried out this study. The stroke model was produced on Sprague-Dawley(SD) rats through middle cerebral artery occlusion(MCAO). Intragastric administration of lactulose substantially increased hydrogen breath concentration. Behavioral and histopathological verifications matched biochemical findings. Behaviorally, rats in lactulose administration group won higher neurological scores and showed shorter escape latency time in Morris test. Morphologically, 2,3,5-triphenyltetrazolium chloride (TTC) showed smaller infarction volume; Nissl staining manifested relatively clear and intact neurons and TUNEL staining showed less apoptotic neurons. Biochemically, lactulose decreased brain malondialdehyde(MDA) content, caspase-3 activity, 3-nitrotyrosine(3-NT) and 8-hydroxy-2-deoxyguanosine(8-OHdG) concentration and increased superoxide dismutase(SOD) activity. And the effects of lactulose were superior to edaravone. Lactulose orally administered activated the expression of NF-E2-related factor 2(Nrf2) in the brain verified by RT-PCR and Western blot. The antibiotics suppressed the neuroprotective effects of lactulose via reducing hydrogen production. Our study for the first time demonstrated a novel therapeutic effect of lactulose on cerebral ischemia/reperfusion injury and the probable underlying mechanisms. Lactulose intragastrically administered possessed neuroprotective effects on cerebral I/R injury in rats, which could be attributed to hydrogen production by the fermentation of lactulose through intestinal bacteria and Nrf2 activation.