Anticonvulsant action of a selective phosphatidylinositol-3-kinase inhibitor LY294002 in pentylenetetrazole-mediated convulsions in zebrafish

The role of PI3K/AKT/mTOR signalling pathway has been widely deciphered in pathogenesis of epilepsy. LY294002 is a selective inhibitor of phosphatidylinositol-3-kinase (PI3K). The present study was designed to explore the anticonvulsant potential of LY294002 in a zebrafish model of pentylenetetrazole (PTZ)-mediated convulsions. Zebrafish larvae at 7dpf (days post fertilization) were pre-incubated with varying concentrations of LY294002, prior to PTZ exposure. The adult zebrafish were also exposed to PTZ after intraperitoneal injection with different concentrations of LY294002, followed by gene expression studies in the brain. The hyperactive responses indicated by total distance travelled and the mean speed of larva was drastically decreased, whereas latency to first clonic-like seizure was increased following LY294002 pre-treatment. Additionally, a marked decrease in c-fos expression was also observed in the larvae group exposed to LY294002 in comparison to control. Furthermore, PTZ evoked seizure severity was considerably decreased, while latency to clonic-like seizure was increased in adult zebrafish group treated with 100 nM of LY294002. Furthermore, the occurrence of tonic-like seizures was also reduced in the adult zebrafish treated with LY294002. The mRNA levels of PIK3CA, PIK3R1, AKT1, mTOR, Rps6 and Rps6kb1 in adult zebrafish brain was significantly reduced as compared to vehicle control group. Our results provided conclusive support for the anticonvulsant potential of LY294002.