bay-11-7082 and Infarction--Middle-Cerebral-Artery

Enriched environment (EE) has been shown to promote post-stroke neurogenesis and functional recovery. However, the underlying molecular mechanisms remains poorly understood. Male C57BL/6 mice underwent 60-min middle cerebral artery occlusion (MCAO) followed by reperfusion, after which mice were housed in either standard environment (SE) or EE. We found that post-ischemic EE exhibited reduced protein level of nuclear factor κB (NF-κB)/p65 in cytoplasm and increased its expression correspondingly in nucleus at 28 days post-ischemia (dpi). However, post-ischemic EE had no effects on terminal deoxynucleotidyl transferase biotin-dUTP nick end labeling (TUNEL)-positive cells in ischemic hemisphere at 28dpi. EE mice treated with NF-kB inhibitor Bay11-7082 had decreased subventricular zone (SVZ) neural precursor cells (NPCs) proliferation, neuronal differentiation and subsequent functional recovery after stroke at 28dpi. Bay11-7082 treatment attenuated the promoting effects of post-ischemic EE on interleukin 17A (IL-17A) messenger RNA (mRNA) and protein expression at 28dpi. Furthermore, our in vitro data revealed that in primary astrocyte cultures addition of Bay11-7082 markedly decreased the expression of IL-17A in both the cell lysate and culture supernatant of activated astrocytes. Blockade of IL-17A with neutralizing antibody abrogated the promoting role of EE in NPCs proliferation derived from SVZ, neuronal differentiation and subsequent functional recovery after stroke. Thus, our results reveal a previously uncharacterized property of NF-κB/IL-17A signaling pathway in EE-mediated neurogenesis and functional recovery after ischemic stroke.

Topics: Animals; Apoptosis; Astrocytes; Bromodeoxyuridine; Disease Models, Animal; Doublecortin Domain Proteins; Environment; Gene Expression Regulation; Infarction, Middle Cerebral Artery; Interleukin-17; Male; Mice; Mice, Inbred C57BL; Microtubule-Associated Proteins; Motor Activity; Neurogenesis; Neuropeptides; NF-kappa B; Nitriles; Protein Transport; RNA, Messenger; Sulfones; Time Factors

Stroke, a leading cause of adult disability in the world, is a severe medical condition with limited treatment. Physical therapy, the only treatment available for stroke rehabilitation, appears to be effective within 6 months post-stroke. Here, we have mechanistically determined the efficacy of combined two hematopoietic growth factors, stem cell factor (SCF) and granulocyte-colony stimulating factor (G-CSF; SCF + G-CSF), in brain repair 6 months after cortical infarct induction in the transgenic mice carrying yellow fluorescent protein in Layer V pyramidal neurons (Thy1-YFP-H). Using a combination of live brain imaging, whole brain imaging, molecular manipulation, synaptic and vascular assessments, and motor function examination, we found that SCF + G-CSF promoted mushroom spine formation, enlarged postsynaptic membrane size, and increased postsynaptic density-95 accumulation and blood vessel density in the peri-infarct cavity cortex; and that SCF + G-CSF treatment improved motor functional recovery. The SCF + G-CSF-enhanced motor functional recovery was dependent on the synaptic and vascular regeneration in the peri-infarct cavity cortex. These data suggest that a stroke-damaged brain is repairable by SCF + G-CSF even 6 months after the lesion occurs. This study provides novel insights into the development of new restorative strategies for stroke recovery.

Topics: Animals; Brain; Dendritic Spines; Disease Models, Animal; Disks Large Homolog 4 Protein; Enzyme Inhibitors; Functional Laterality; Gene Expression Regulation; Granulocyte Colony-Stimulating Factor; Infarction, Middle Cerebral Artery; Intracellular Signaling Peptides and Proteins; Male; Membrane Proteins; Mice; Mice, Transgenic; Motor Activity; Neurons; Nitriles; Phosphopyruvate Hydratase; Platelet Endothelial Cell Adhesion Molecule-1; Recovery of Function; Regeneration; Sulfones; Transcription Factor RelA