Research reportTRPC3- and ETB receptor-mediated PI3K/AKT activation induces vasogenic edema formation following status epilepticus

- SE increases TRPC3-mediated PI3K/AKT phosphorylation in the PC.
- ETB receptor also increases SE-induced PI3K/AKT phosphorylation.
- NFκB inhibitor abolishes both TRPC3- and ETB receptor-mediated PI3K/AKT phosphorylation.
- Inhibition of VEGF over-expression reduces TRPC3-mediated PI3K/AKT phosphorylation.
- PI3K/AKT inhibitors attenuates vasogenic edema by abrogating eNOS activation.

Status epilepticus (SE, a prolonged seizure activity) is a high risk factor of developing vasogenic edema, which leads to secondary complications following SE. In the present study, we investigated whether transient receptor potential canonical channel-3 (TRPC3) may link vascular endothelial growth factor (VEGF) pathway to NFκB/ETB receptor axis in the rat piriform cortex during vasogenic edema formation. Following SE, TRPC3 and ETB receptor independently activated phosphatidylinositol 3 kinase (PI3K)/AKT/eNOS signaling pathway. SN50 (a NFκB inhibitor) attenuated the up-regulations of eNOS, TRPC3 and ETB receptor expressions following SE, accompanied by reductions in PI3K/AKT phosphorylations. Inhibition of SE-induced VEGF over-expression by leptomycin B also abrogated PI3K and AKT phosphorylations, but not TRPC3 expression. Wortmannin (a PI3K inhibitor) and 3CAI (an AKT inhibitor) effectively inhibited up-regulation of eNOS expressions and vasogenic edema lesion following SE. These findings indicate that PI3K/AKT may be common down-stream molecules for TRPC3- and ETB receptor signaling pathways during vasogenic edema formation. In addition, the present data demonstrate for the first time that TRPC3 may integrate VEGF- and NFκB-mediated vasogenic edema formation following SE. Thus, we suggest that PI3K/AKT signaling pathway may be one of considerable therapeutic targets for vasogenic edema.