PMID- 25324012 OWN - NLM STAT- MEDLINE DCOM- 20160808 LR - 20211021 IS - 1559-1182 (Electronic) IS - 0893-7648 (Linking) VI - 52 IP - 3 DP - 2015 Dec TI - Gadd45b Mediates Axonal Plasticity and Subsequent Functional Recovery After Experimental Stroke in Rats. PG - 1245-1256 LID - 10.1007/s12035-014-8909-0 [doi] AB - 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. FAU - Liu, Bin AU - Liu B AD - Department of Neurology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China. FAU - Li, Long-Ling AU - Li LL AD - Department of Neurology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China. FAU - Tan, Xiao-Dan AU - Tan XD AD - Department of Neurology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China. FAU - Zhang, Yan-Hong AU - Zhang YH AD - Department of Neurology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China. FAU - Jiang, Ying AU - Jiang Y AD - Department of Neurology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China. FAU - He, Guo-Qian AU - He GQ AD - Department of Neurology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China. FAU - Chen, Qian AU - Chen Q AD - Department of Neurology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China. FAU - Li, Chang-Qing AU - Li CQ AD - Department of Neurology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China. licq9218@163.com. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20141017 PL - United States TA - Mol Neurobiol JT - Molecular neurobiology JID - 8900963 RN - 0 (Antigens, Differentiation) RN - 0 (Brain-Derived Neurotrophic Factor) RN - 0 (Cyclic AMP Response Element-Binding Protein) RN - 0 (Gadd45b protein, rat) RN - 0 (RNA, Messenger) RN - 0 (RNA, Small Interfering) RN - EC 2.7.11.1 (rho-Associated Kinases) SB - IM MH - Animals MH - Antigens, Differentiation/genetics/*physiology MH - Axons/physiology MH - Brain-Derived Neurotrophic Factor/biosynthesis/genetics MH - Cyclic AMP Response Element-Binding Protein/biosynthesis/genetics MH - Gene Expression Regulation MH - Infarction, Middle Cerebral Artery/*physiopathology MH - Male MH - Nerve Regeneration/*physiology MH - Neuronal Plasticity/*physiology MH - RNA Interference MH - RNA, Messenger/biosynthesis/genetics MH - RNA, Small Interfering/genetics MH - Random Allocation MH - Rats MH - Rats, Sprague-Dawley MH - Recovery of Function MH - Signal Transduction/physiology MH - rho-Associated Kinases/biosynthesis/genetics OTO - NOTNLM OT - Axonal plasticity OT - BDNF OT - Gadd45b OT - Middle cerebral artery occlusion EDAT- 2014/10/18 06:00 MHDA- 2016/08/09 06:00 CRDT- 2014/10/18 06:00 PHST- 2014/06/06 00:00 [received] PHST- 2014/09/28 00:00 [accepted] PHST- 2014/10/18 06:00 [entrez] PHST- 2014/10/18 06:00 [pubmed] PHST- 2016/08/09 06:00 [medline] AID - 10.1007/s12035-014-8909-0 [pii] AID - 10.1007/s12035-014-8909-0 [doi] PST - ppublish SO - Mol Neurobiol. 2015 Dec;52(3):1245-1256. doi: 10.1007/s12035-014-8909-0. Epub 2014 Oct 17.