title: [Gly14]-Humanin offers neuroprotection through glycogen synthase kinase-3β inhibition in a mouse model of intracerebral hemorrhage.
abstract: Perihematomal brain edema formation and consequent cell death contribute to second brain injury resulting in severe neurological deficits and sometimes delayed fatality after intracerebral hemorrhage (ICH). [Gly14]-Humanin (HNG), a variant of Humanin (HN) in which the 14th amino acid serine is replaced with glycine, reduced Alzheimer's disease-relevant insults and improved neurological deficits in an ischemia stroke model. In the study, we aimed to evaluate whether HNG posttreatment attenuated early brain injury after ICH and whether the protective effect was associated with regulation of apoptosis via phosphatidylinositol 3-kinase (PI3K)-Akt/GSK-3β signaling. Male ICR mice were subjected to infusion of Type IV collagenase (to induce ICH) of saline (for shams) into the left striatum. ICH animals received vehicle, HNG (1 or 2.5 μg in 100 μl saline) administration intraperitoneally 1h post injury. Compared with vehicle, HNG-2.5 μg treatment improved neurological outcome and reduced brain edema at 24 and 72 h after surgery (P<0.05), but wortmannin (15 μg/kg, 90 min before HNG-2.5 μg, intravenously) obliterated the effect. HNG-2.5 μg also reduced cell insults and injury volume at 24 and 72 h after surgery (P<0.05, vs. vehicle). Furthermore, HNG-2.5 μg treatment increased p-Akt and Bcl-2 and decreased p-GSK-3β, cleaved caspase-3 and cleaved poly (ADP-ribose) polymerase expressions in the ipsilateral hemisphere (P<0.05, vs. vehicle), however, the effect was reversed by wortmannin. In conclusion, HNG treatment improved functional and morphological outcomes after experimental ICH in mice and the protective effect was associated with suppressing apoptosis through PI3K-Akt/GSK-3β signaling pathway.
authors.affiliation: Department of Forensic Science, Medical School of Soochow University, Suzhou 215123, China.
authors.forename: Tao
authors.initials: T
authors.lastname: Wang
authors.forename: Ya
authors.initials: Y
authors.lastname: Huang
authors.forename: Mingyang
authors.initials: M
authors.lastname: Zhang
authors.forename: Long
authors.initials: L
authors.lastname: Wang
authors.forename: Yaoqi
authors.initials: Y
authors.lastname: Wang
authors.forename: Lu
authors.initials: L
authors.lastname: Zhang
authors.forename: Wenwen
authors.initials: W
authors.lastname: Dong
authors.forename: Pan
authors.initials: P
authors.lastname: Chang
authors.forename: Zufeng
authors.initials: Z
authors.lastname: Wang
authors.forename: Xiping
authors.initials: X
authors.lastname: Chen
authors.forename: Luyang
authors.initials: L
authors.lastname: Tao
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D002543:Cerebral Hemorrhage / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D047908:Intracellular Signaling Peptides and Proteins / Q000494:pharmacology / Q000627:therapeutic use*; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D009474:Neurons / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D018696:Neuroprotective Agents / Q000494:pharmacology / Q000627:therapeutic use*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; D018696:Neuroprotective Agents; D019253:Proto-Oncogene Proteins c-bcl-2; C427211:humanin; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D051057:Proto-Oncogene Proteins c-akt; D038362:Glycogen Synthase Kinase 3