Previous studies have suggested that thrombospondin-1 (TSP-1) regulates the transforming growth factor beta 1 (TGF-β1)/phosphorylated Smad2/3 (pSmad2/3) pathway.Moreover,TSP-1 is closely associated with epilepsy.However,the role of the TSP-1-regulated TGF-β1/pSmad2/3 pathway in seizures remains unclear.In this study,changes in this pathway were assessed following kainic acid (KA)-induced status epilepticus (SE) in rats.The results showed that increases in the TSP-1/TGF-β1/pSmad2/3 levels spatially and temporally matched the increases in glial fibrillary acidic protein (GFAP)/chondroitin sulfate (CS56) levels following KA administration.Inhibition of TSP-1 expression by small interfering RNA or inhibition of TGF-β1 activation with a Leu-Ser-Lys-Leu peptide significantly reduced the severity of KA-induced acute seizures.These anti-seizure effects were accompanied by decreased GFAP/CS56 expression and Smad2/3 phosphorylation.Moreover,inhibiting Smad2/3 phosphorylation with ponatinib or SIS3 also significantly reduced seizure severity,alongside reducing GFAP/CS56 immunoreactivity.These results suggest that the TSP-1-regulated TGF-β1/pSmad2/3 pathway plays a key role in KA-induced SE and astrogliosis,and that inhibiting this pathway may be a potential anti-seizure strategy.