title: Gadd45b Mediates Axonal Plasticity and Subsequent Functional Recovery After Experimental Stroke in Rats.
abstract: Stroke causes devastating and irreversible losses of neurological function with subsequent slow and incomplete recovery of lost brain functions, because of the brain's limited capacity for brain plasticity. Growth arrest and DNA-damage-inducible protein 45 beta (Gadd45b) has recently been demonstrated as a candidate plasticity-related gene, making it an excellent candidate molecule that has therapeutic potential. Here, we examine whether in vivo blockage of Gadd45b affects axonal plasticity and subsequent functional recovery after focal brain infarction. Adult male Sprague-Dawley rats were subjected to cerebral ischemia by middle cerebral artery occlusion (MCAO). We adopted RNA interference (RNAi) mediated by a lentiviral vector (LV) as a means of suppressing the expression of Gadd45b. Functional recovery was assessed with a battery of tests that measured skilled forelimb reaching and forelimb balance controlling. Axonal reorganization at the level of the red nucleus was revealed by anatomical studies. Axonal regeneration was measured by elevated expression of growth-associated protein 43 (GAP-43). The levels of brain-derived neurotrophic factor (BDNF), cyclic AMP (cAMP), protein kinase A (PKA), and Rho-kinase (ROCK) were determined. Gadd45b-RNAi significantly inhibited axonal plasticity (axonal regeneration and axonal reorganization) after MCAO. This inhibition was paralleled by worse functional recovery performance on several behavioral measures. Gadd45b-RNAi also significantly decreased the expression levels of both BDNF and cAMP/PKA/phosphorylated cAMP response element-binding protein (pCREB) pathway and promoted ROCK expression. We conclude that Gadd45b stimulates recovery after stroke by enhancing axonal plasticity required for brain repair. Pharmacological targeting of Gadd45b provides new opportunities for stroke treatment.
authors.affiliation: Department of Neurology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China.
authors.forename: Bin
authors.initials: B
authors.lastname: Liu
authors.affiliation: Department of Neurology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China.
authors.forename: Long-Ling
authors.initials: LL
authors.lastname: Li
authors.affiliation: Department of Neurology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China.
authors.forename: Xiao-Dan
authors.initials: XD
authors.lastname: Tan
authors.affiliation: Department of Neurology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China.
authors.forename: Yan-Hong
authors.initials: YH
authors.lastname: Zhang
authors.affiliation: Department of Neurology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Jiang
authors.affiliation: Department of Neurology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China.
authors.forename: Guo-Qian
authors.initials: GQ
authors.lastname: He
authors.affiliation: Department of Neurology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China.
authors.forename: Qian
authors.initials: Q
authors.lastname: Chen
authors.affiliation: Department of Neurology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China. licq9218@163.com.
authors.forename: Chang-Qing
authors.initials: CQ
authors.lastname: Li
mesh_terms: D000818:Animals; D000943:Antigens, Differentiation / Q000235:genetics / Q000502:physiology*; D001369:Axons / Q000502:physiology; D019208:Brain-Derived Neurotrophic Factor / Q000096:biosynthesis / Q000235:genetics; D017362:Cyclic AMP Response Element-Binding Protein / Q000096:biosynthesis / Q000235:genetics; D005786:Gene Expression Regulation; D020244:Infarction, Middle Cerebral Artery / Q000503:physiopathology*; D008297:Male; D009416:Nerve Regeneration / Q000502:physiology*; D009473:Neuronal Plasticity / Q000502:physiology*; D034622:RNA Interference; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D020127:Recovery of Function; D015398:Signal Transduction / Q000502:physiology; D054460:rho-Associated Kinases / Q000096:biosynthesis / Q000235:genetics; D000097642:GADD45 Proteins
chemical_list: D000943:Antigens, Differentiation; D019208:Brain-Derived Neurotrophic Factor; D017362:Cyclic AMP Response Element-Binding Protein; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D054460:rho-Associated Kinases; C508094:Gadd45b protein, rat; D000097642:GADD45 Proteins
keywords: Axonal plasticity; BDNF; Gadd45b; Middle cerebral artery occlusion