Antispasmodic Drug Drofenine as an Inhibitor of Kv2.1 Channel Ameliorates Peripheral Neuropathy in Diabetic Mice

Abstract

Summary Diabetic peripheral neuropathy (DPN) is a common diabetic complication and has yet no efficient medication. Here, we report that antispasmodic drug drofenine (Dfe) blocks Kv2.1 and ameliorates DPN-like pathology in diabetic mice. The underlying mechanisms are investigated against the DPN mice with in vivo Kv2.1 knockdown through 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 a suppressed neurite outgrowth in DRG neuron. Dfe promoted neurite outgrowth by inhibiting Kv2.1 channel and/or Kv2.1 mRNA and protein expression level. Moreover, it suppressed inflammation by repressing IκBα/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. Our work supports that Kv2.1 inhibition is a promisingly therapeutic strategy for DPN and highlights the potential of Dfe in treating this disease.

Lysine demethylase KDM5B down‐regulates SIRT3‐mediated mitochondrial glucose and lipid metabolism in diabetic neuropathy

“…Neurophysiological assessment was performed on db/db mice and db/m mice aged 18–24 weeks by detecting motor nerve conduction velocity (MNCV) as previously reported 17 . Briefly, mice were placed on a heated pad to maintain a stationary rectal temperature of 37°C and then anesthetized by intraperitoneal injection of 50 mg/kg sodium pentobarbital.…”

“…Neurophysiological assessment was performed on db/ db mice and db/m mice aged 18-24 weeks by detecting motor nerve conduction velocity (MNCV) as previously reported. 17 Briefly, mice were placed on a heated pad to maintain a stationary rectal temperature of 37°C and then anesthetized by intraperitoneal injection of 50 mg/kg sodium pentobarbital. MNCV was detected after stimulation by bipolar electrodes and calculated by the following formula: distance between two points (cm) × 10/latency difference between two points.…”

PGC1α: an emerging therapeutic target for chemotherapy-induced peripheral neuropathy

“… 71 Salvianolic acid A application and potassium voltage-gated channel subfamily B member 1 (Kv2.1) inhibition protect the peripheral nerve function in diabetic rats through the regulation of the AMPK/PGC1α pathway. 72 , 73 Furthermore, overexpression of human TFAM in mice can prevent type 1 diabetes-induced nerve conduction slowdown, improve epidermal fiber loss, and alleviate mechanical hyperalgesia. 74 As an upstream regulator of TFAM, knockout of PGC1α leads to mitochondrial damage, increases oxidative stress, leads to mitochondrial dysfunction, and exacerbates diabetic neuropathy.…”