Gadd45b Mediates Axonal Plasticity and Subsequent Functional Recovery After Experimental Stroke in Rats

• DOI: 10.1007/s12035-014-8909-0
• Publication Date: 2014-10-16T05:33:16Z
• Authors: Bin Liu; Long-ling Li; Xiao-dan Tan; Yan-hong Zhang; Ying Jiang; Guo-qian He; Qian Chen; Chang-qing Li
• Keywords: Male; 0301 basic medicine; rho-Associated Kinases; Neuronal Plasticity; Brain-Derived Neurotrophic Factor; Infarction, Middle Cerebral Artery; Recovery of Function; Antigens, Differentiation; Axons; Nerve Regeneration; Rats; Rats, Sprague-Dawley; Random Allocation; 03 medical and health sciences; Gene Expression Regulation; Animals; RNA Interference; RNA, Messenger; RNA, Small Interfering; Cyclic AMP Response Element-Binding Protein; Signal Transduction

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.