FSC231 alleviates paclitaxel-induced neuralgia by inhibiting the interactions between PICK1 and GluA2 and activates GSK-3β and ERK1/2

Background: FSC231, a PSD-95/DLG/ZO-1 (PDZ) domain inhibitor of protein kinase Cα interacting protein 1 (PICK1), has analgesic effects, but the mechanism remains unclear.

Methods: The expression level of PICK1 in dorsal root ganglion (DRG) of rats was changed by vector plasmid, and the effect of PICK1 on paclitaxel (PTL)-induced neuralgia of rats was observed in collaboration with FSC231 treatment. The possible molecular mechanisms were explored by quantitative real-time polymerase chain reaction (qRT-PCR), Western Blot and co-immunoprecipitation (Co-IP) techniques.

Results: PTL treatment can significantly reduce mechanical withdrawal threshold (MWT), shorten thermal withdrawal latency (TWL), promote DRG inflammation and release of substance P (SP), stimulate PICK1 expression, decrease α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid receptor 2 (AMPAR, GluA2) level and increase glycogen synthase kinase-3β (GSK-3β) and extracellular regulated protein kinases1/2 (ERK1/2) phosphorylation in rats, while FSC231 treatment can alleviate the above effects induced by PTL. Overexpression of PICK1 can counteract reduced PICK1 level, increased GluA2 level and decreased GSK-3β and ERK1/2 phosphorylation levels caused by FSC231 treatment. The results of Co-IP confirmed the interactions between PICK1 and GluA2. Both FSC231 treatment and silent PICK1 improved PTL-induced MWT reduction, TWL shortening, inflammation, SP release and related gene expression changes, with cumulative effect.

Conclusion: FSC231 activates GSK-3β/ERK1/2 by inhibiting the interaction between PICK1 and GluA2 and alleviates PTL-induced DRG neuralgia in rats.