Antispasmodic drug drofenine as an inhibitor of Kv2.1 channel ameliorates peripheral neuropathy in diabetic mice
Description
Here, we report that the antispasmodic drug drofenine (Dfe) blocks Kv2.1 with an IC50 of 9.3 M, and in vivo treatment with Dfe suppresses mRNA and protein expression of Kv2.1 in DRG tissues of DPN mice and ameliorates DPN-like pathology. The underlying mechanisms have been intensively investigated by assay against the DPN mice with in vivo Kv2.1 knockdown injected with adeno associated virus AAV9-Kv2.1-RNAi. Streptozotocin (STZ) induced type 1 or db/db type 2 diabetic mice with DPN exhibited a high level of Kv2.1 protein in dorsal root ganglion (DRG) tissue and suppressed neurite outgrowth in DRG neuron. Dfe treatment promoted neurite outgrowth by inhibiting Kv2.1 channel. Moreover, it suppressed inflammation by repressing IB/NF-κB signaling, inhibited apoptosis by regulating Kv2.1-mediated Bcl-2 family proteins and Caspase 3 and ameliorated mitochondrial dysfunction through Kv2.1/CaMKKβ/AMPK/PGC1α pathway. Together, our work has strongly supported that Kv2.1 inhibition is a promising therapeutic strategy for DPN and highlighted the potential of Dfe in the treatment of this disease.