Send to

Choose Destination
Brain Res Bull. 2019 Jul;149:106-119. doi: 10.1016/j.brainresbull.2019.04.004. Epub 2019 Apr 18.

P2Y4/TSP-1/TGF-β1/pSmad2/3 pathway contributes to acute generalized seizures induced by kainic acid.

Author information

School of Pharmaceutical Sciences, Binzhou Medical University, Yantai, China.
Shandong Academy of Medical Sciences, Jinan, China.
School of Pharmaceutical Sciences, Binzhou Medical University, Yantai, China. Electronic address:


Epilepsy is accompanied by angiogenesis and blood-brain barrier (BBB) disruption. The transforming growth factor-β1 (TGF-β1)/phosphorylated small mothers against decapentaplegic 2 and 3 (pSmad2/3)/vascular endothelial growth factor (VEGF) pathway, activated by thrombospondin-1 (TSP-1), which is further regulated by Y type P2 purinergic receptor activity, may participate in angiogenesis. We sought to investigate the relationship between the P2R/TSP-1/TGF-β1/pSmad2/3/VEGF pathway, angiogenesis, and BBB damage in a kainic acid (KA) model of acute generalized seizure. Our results demonstrated that KA-induced seizures were accompanied by angiogenesis and BBB damage. In addition, expression of TSP-1, TGF-β1, and pSmad2/3 was increased. Rats treated with pyridoxal phosphate-6-azophenyl-2', 4'-disulfonic acid, a broad P2 receptor antagonist, or Reactive Blue 2, a potent P2Y4 receptor antagonist, showed significant attenuation of TSP-1 expression and Smad2/3 phosphorylation levels. Furthermore, angiogenesis, BBB damage, and acute seizure severity were also reduced. The inhibition of TSP-1 expression by siRNA or TGF-β1 activation by Leu-Ser-Lys-Leu (LSKL) treatment prevented KA-induced phosphorylation of Smad2/3, angiogenesis, BBB damage, and acute seizures. Our results strongly indicate that the P2Y4/TSP-1/TGF-β1/pSmad2/3/VEGF pathway plays an essential role in seizure pathophysiology and angiogenesis. Therapeutic interventions targeting this pathway may offer new treatment options for acute seizures.


Angiogenesis; Purinergic receptor 2; Seizure; Thrombospondin-1

Supplemental Content

Full text links

Icon for Elsevier Science
Loading ...
Support Center