title: Lactulose ameliorates cerebral ischemia-reperfusion injury in rats by inducing hydrogen by activating Nrf2 expression.
abstract: Molecular hydrogen has been proven effective in ameliorating cerebral ischemia/reperfusion (I/R) injury by selectively neutralizing reactive oxygen species. Lactulose can produce a 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 in Sprague-Dawley rats through middle cerebral artery occlusion. Intragastric administration of lactulose substantially increased breath hydrogen concentration. Behavioral and histopathological verifications matched biochemical findings. Behaviorally, rats in the lactulose administration group won higher neurological scores and showed shorter escape latency time in the Morris test. Morphologically, 2,3,5-triphenyltetrazolium chloride showed smaller infarction volume; Nissl staining manifested relatively clear and intact neurons and TUNEL staining showed fewer apoptotic neurons. Biochemically, lactulose decreased brain malondialdehyde content, caspase-3 activity, and 3-nitrotyrosine and 8-hydroxy-2-deoxyguanosine concentration and increased superoxide dismutase activity. The effects of lactulose were superior to those of edaravone. Lactulose orally administered activated the expression of NF-E2-related factor 2 (Nrf2) in the brain as verified by RT-PCR and Western blot. The antibiotics suppressed the neuroprotective effects of lactulose by reducing hydrogen production. Our study for the first time demonstrates 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.
authors: Graduate Management Unit, Changhai Hospital affiliated with the Second Military Medical University, Shanghai 200433, People's Republic of China; Graduate Management Unit, Second Military Medical University, Shanghai 200433, People's Republic of China.
authors: Xiao
authors: X
authors: Zhai
authors: Graduate Management Unit, Changhai Hospital affiliated with the Second Military Medical University, Shanghai 200433, People's Republic of China; Graduate Management Unit, Second Military Medical University, Shanghai 200433, People's Republic of China.
authors: Xiao
authors: X
authors: Chen
authors: Graduate Management Unit, Second Military Medical University, Shanghai 200433, People's Republic of China.
authors: Jiazi
authors: J
authors: Shi
authors: Department of Biochemical Pharmacy, Faculty of Pharmacy, Second Military Medical University, Shanghai 200433, People's Republic of China.
authors: Duo
authors: D
authors: Shi
authors: Department of Diving Medicine, Faculty of Naval Medicine, Second Military Medical University, Shanghai 200433, People's Republic of China.
authors: Zhouheng
authors: Z
authors: Ye
authors: Department of Diving Medicine, Faculty of Naval Medicine, Second Military Medical University, Shanghai 200433, People's Republic of China.
authors: Wenwu
authors: W
authors: Liu
authors: Department of Orthopedics, Changhai Hospital affiliated with the Second Military Medical University, Shanghai 200433, People's Republic of China.
authors: Ming
authors: M
authors: Li
authors: Department of Endocrinology, Changhai Hospital affiliated with the Second Military Medical University, Shanghai 200433, People's Republic of China.
authors: Qijin
authors: Q
authors: Wang
authors: Department of Diving Medicine, Faculty of Naval Medicine, Second Military Medical University, Shanghai 200433, People's Republic of China.
authors: Zhimin
authors: Z
authors: Kang
authors: Department of Plastic Surgery, Changhai Hospital affiliated with the Second Military Medical University, Shanghai 200433, People's Republic of China. Electronic address: sunxjk@hotmail.com.
authors: Hongda
authors: H
authors: Bi
authors: Department of Diving Medicine, Faculty of Naval Medicine, Second Military Medical University, Shanghai 200433, People's Republic of China. Electronic address: jsjyzx8@qq.com.
authors: Xuejun
authors: X
authors: Sun
mesh_terms: D000818:Animals; D015153:Blotting, Western; D001921:Brain / Q000187:drug effects; D002545:Brain Ischemia / Q000378:metabolism*; D006859:Hydrogen / Q000378:metabolism*; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D007792:Lactulose / Q000378:metabolism / Q000494:pharmacology*; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D051267:NF-E2-Related Factor 2 / Q000378:metabolism*; D018696:Neuroprotective Agents / Q000378:metabolism / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D060888:Real-Time Polymerase Chain Reaction; D015427:Reperfusion Injury / Q000378:metabolism*
chemical_list: D051267:NF-E2-Related Factor 2; D018696:Neuroprotective Agents; C495637:Nfe2l2 protein, rat; D007792:Lactulose; D006859:Hydrogen
keywords: 2,3,5-triphenyltetrazolium chloride; 3-NT; 3-nitrotyrosine; 8-OHdG; 8-hydroxy-2-deoxyguanosine; ANTI; Antioxidant; ECA; Ed; Free radicals; Hydrogen; I/R; ICA; Ischemia/reperfusion; LAC; Lactulose; MCAO; MDA; NF-E2-related factor 2; Nrf2; PBS; PD; Parkinson disease; ROS; SOD; TTC; TUNEL; antibiotics; edaravone; external carotid artery; internal carotid artery; ischemia/reperfusion; lactulose; malondialdehyde; middle cerebral artery occlusion; phosphate-buffered saline; qRT-PCR; quantitative reverse transcription–PCR; reactive oxygen species; superoxide dismutase; terminal deoxynucleotidyl transferase dUTP nick-end labeling