Salvianolic acid A improves chronic cerebral ischemia through TLR4/MAPKs/AP-1 signaling pathway

Abstract Chronic cerebral hypoperfusion (CCH) is a clinical syndrome. Long-term chronic cerebral low perfusion will lead to insufficient blood supply to the brain, this leads to a pathological cascade. Salvianolic acid A (SAA) is a water-soluble phenolic acid contained in Salvia miltiorrhiza Bge., which has regulated effect on cardiovascular and cerebrovascular diseases. We established a chronic bilateral common carotid artery occlusion (BCCAO) model to investigate the improvement of SAA on cognitive dysfunction after chronic cerebral ischemia, and further explore whether it has a protective effect on hippocampal neuron damage. The mRNA changes of BCCAO model rats before and after SAA administration were analyzed based on RNA-Seq technique. Combined with GO and KEGG analysis results, PPI network analysis was performed for the major differential genes. Finally, the results were verified by western blot and enzyme-linked immunosorbent assay. After SAA treatment in BCCAO rats, behavioral experiments showed that SAA could improve learning and memory dysfunction caused by BCCAO model in rats. Moreover, it can significantly improve the hippocampal damage caused by long-term cerebral ischemia. Differential gene analysis revealed that there were multiple gene and pathway changes before and after SAA treatment. The genes we screened included TLR4, MyD88, Fos, Jun, ERK1/2, JNK and P38. Western blotting and enzyme-linked immunosorbent assay showed that SAA could regulate the TLR4/MAPKS/AP-1 signaling pathway, reduce the release of inflammatory factors, improve the nerve injury caused by brain ischemia in rats, and playing neuroprotective effects.