Gadd45b Mediates Axonal Plasticity and Subsequent Functional Recovery After Experimental Stroke in Rats
| Autor: | Guo-qian He, Longling Li, Xiao-dan Tan, Bin Liu, Ying Jiang, Qian Chen, Changqing Li, Yanhong Zhang |
|---|---|
| Rok vydání: | 2014 |
| Předmět: |
Male
Red nucleus Neuroscience (miscellaneous) Ischemia Biology Rats Sprague-Dawley Random Allocation Cellular and Molecular Neuroscience Neurotrophic factors Neuroplasticity medicine Animals RNA Messenger RNA Small Interfering Cyclic AMP Response Element-Binding Protein Protein kinase A rho-Associated Kinases Neuronal Plasticity Brain-Derived Neurotrophic Factor Regeneration (biology) Infarction Middle Cerebral Artery Recovery of Function medicine.disease Antigens Differentiation Axons Nerve Regeneration Rats medicine.anatomical_structure Gene Expression Regulation Neurology RNA Interference GADD45B Forelimb Neuroscience Signal Transduction |
| Zdroj: | Molecular Neurobiology. 52:1245-1256 |
| ISSN: | 1559-1182 0893-7648 |
| DOI: | 10.1007/s12035-014-8909-0 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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