title: Lithium posttreatment confers neuroprotection through glycogen synthase kinase-3β inhibition in intracerebral hemorrhage rats.
abstract: OBJECTIVE Inflammation and apoptosis are two key factors contributing to secondary brain injury after intracerebral hemorrhage (ICH). The objective of this study was to evaluate the effects of lithium posttreatment on behavior, brain atrophy, inflammation, and perihematomal cell death. Furthermore, the authors aimed to determine the role of the pro-apoptotic glycogen synthase kinase-3β (GSK-3β) after experimental ICH. METHODS Male Sprague-Dawley rats (n = 108) were subjected to intracerebral infusion of semicoagulated autologous blood. Window of opportunity and dose optimization studies of lithium on ICH-induced injury were performed by measuring neurological deficits. Animals with ICH received vehicle administration or lithium posttreatment (60 mg/kg) for up to 21 days. Hemispheric atrophy was evaluated. Perihematomal cell death was quantified through terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling (TUNEL). The number of myeloperoxidase (MPO)-positive neutrophils and OX42-positive microglia in the perihematomal areas were calculated. Western blotting was used for the quantification of GSK-3β, heat shock protein 70 (HSP70), nuclear factor-κB p65 (NF-κB p65), and cy-clooxygenase-2 (COX-2). RESULTS Lithium, at a dose of 60 mg/kg initiated from 2 hours after injury, exhibited the best effects of improving neurological outcomes 3, 5, 7, 14, 21, and 28 days after ICH, reduced the hemispheric atrophy at 42 days after surgery, and reduced the number of TUNEL-positive cells, MPO-positive neutrophils, and OX42-positive microglia in the perihematomal areas. Furthermore, lithium posttreatment modulated GSK-3β, increased HSP70, and decreased NF-κB p65 and COX-2 expression in the ipsilateral hemisphere. CONCLUSIONS Lithium posttreatment at a dose of 60 mg/kg, initiated beginning 2 hours after injury, improves functional and morphological outcomes, and inhibits inflammation and perihematomal cell death in a rat model of semicoagulated autologous blood ICH through inactivation of GSK-3β.
authors.affiliation: Department of Biopharmaceutical Sciences, College of Pharmacy, Harbin Medical University, Heilongjiang.
authors.forename: Jian
authors.initials: J
authors.lastname: Zheng
authors.affiliation: Department of Biopharmaceutical Sciences, College of Pharmacy, Harbin Medical University, Heilongjiang.
authors.forename: Zhen
authors.initials: Z
authors.lastname: Liu
authors.affiliation: Department of Biopharmaceutical Sciences, College of Pharmacy, Harbin Medical University, Heilongjiang.
authors.forename: Weishan
authors.initials: W
authors.lastname: Li
authors.affiliation: The Ninth People's Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai; and.
authors.forename: Jiaxin
authors.initials: J
authors.lastname: Tang
authors.affiliation: Department of General Surgery, The Second Affiliated Hospital of Harbin Medical University, Heilongjiang, China.
authors.forename: Dongwei
authors.initials: D
authors.lastname: Zhang
authors.affiliation: Department of Biopharmaceutical Sciences, College of Pharmacy, Harbin Medical University, Heilongjiang.
authors.forename: Xiaobo
authors.initials: X
authors.lastname: Tang
mesh_terms: D000818:Animals; D002543:Cerebral Hemorrhage / Q000188:drug therapy*; D000071679:Glycogen Synthase Kinase 3 beta / Q000037:antagonists & inhibitors*; D018020:Lithium Compounds / Q000008:administration & dosage*; D008297:Male; D000066829:Neuroprotection / Q000187:drug effects*; D018696:Neuroprotective Agents / Q000008:administration & dosage*; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D018020:Lithium Compounds; D018696:Neuroprotective Agents; D000071679:Glycogen Synthase Kinase 3 beta
keywords: COX-2 = cyclooxygenase-2; CRMP2 = collapsin response mediator protein 2; GSK-3β = glycogen synthase kinase-3β; HSF-1 = heat-shock factor-1; HSP70 = heat shock protein 70; ICH = intracerebral hemorrhage; MPO = myeloperoxidase; NF-κB = nuclear factor-κB; PBS = phosphate-buffered saline; TBST = Tris-buffered saline with Tween; TUNEL = terminal deoxynucleotidyl transferase–mediated deoxyuridine triphosphate nick-end labeling; apoptosis; glycogen synthase kinase-3β; inflammation; intracerebral hemorrhage; lithium; neurological deficit; p-CRMP2 = phosphorylated-CRMP2; p-GSK-3β = phosphorylated-GSK-3β; p-β-catenin = phosphorylated-β-catenin; vascular disorders