Background Diabetic peripheral neuropathy (DPN) is a common complication of diabetes severely afflicting the patients, while there is yet no effective medication against this disease. As Kv2.1 channel functions potently in regulating neurological disorders, the present work was to investigate the regulation of Kv2.1 channel against DPN-like pathology of DPN model mice by using selective Kv2.1 inhibitor SP6616 (ethyl 5-(3-ethoxy-4-methoxyphenyl)-2-(4-hydroxy-3-methoxybenzylidene)-7-methyl-3-oxo-2,3-dihydro-5H-[1,3]thiazolo[3,2-a]pyrimidine-6-carboxylate) as a probe. Methods STZ-induced type 1 diabetic mice with DPN (STZ mice) were defined at 12 weeks of age (4 weeks after STZ injection) through behavioral tests, and db/db (BKS Cg- m +/+ Lepr db /J ) type 2 diabetic mice with DPN ( db/db mice) were at 18 weeks of age. SP6616 was administered daily via intraperitoneal injection for 4 weeks. The mechanisms underlying the amelioration of SP6616 on DPN-like pathology were investigated by RT-PCR, western blot and immunohistochemistry technical approaches against diabetic mice, and verified against the STZ mice with Kv2.1 knockdown in dorsal root ganglion (DRG) tissue by injection of adeno associated virus AAV9-Kv2.1-RNAi. Amelioration of SP6616 on the pathological behaviors of diabetic mice was assessed against tactile allodynia, thermal sensitivity and motor nerve conduction velocity (MNCV). Findings SP6616 treatment effectively ameliorated the threshold of mechanical stimuli, thermal sensitivity and MNCV of diabetic mice. Mechanism research results indicated that SP6616 suppressed Kv2.1 expression, increased the number of intraepidermal nerve fibers (IENFs), improved peripheral nerve structure and vascular function in DRG tissue. In addition, SP6616 improved mitochondrial dysfunction through Kv2.1/CaMKKβ/AMPK/PGC-1α pathway, repressed inflammatory response by inhibiting Kv2.1/NF-κB signaling and alleviated apoptosis of DRG neuron through Kv2.1-mediated regulation of Bcl-2 family proteins and Caspase-3 in diabetic mice. Interpretation Our work has highly supported the beneficial of Kv2.1 inhibition in ameliorating DPN-like pathology and highlighted the potential of SP6616 in the treatment of DPN. Funding Please see funding sources.
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.
Diabetic peripheral neuropathy (DPN) is a long-term complication of diabetes with a complicated pathogenesis. AMP-activated protein kinase (AMPK) senses oxidative stress, and mitochondrial function plays a central role in the regulation of DPN. Here, we reported that DW14006 (2-[3-(7-chloro-6-[29-hydroxy-(1,19-AMPKa activator efficiently ameliorated DPN in both streptozotocin (STZ)-induced type 1 and BKS db/db type 2 diabetic mice. DW14006 administration highly enhanced neurite outgrowth of dorsal root ganglion neurons and improved neurological function in diabetic mice. The underlying mechanisms have been intensively investigated. DW14006 treatment improved mitochondrial bioenergetics profiles and restrained oxidative stress and inflammation in diabetic mice by targeting AMPKa, which has been verified by assay against the STZ-induced diabetic mice injected with adeno-associated virus 8-AMPKa-RNAi. To our knowledge, our work might be the first report on the amelioration of the direct AMPKa activator on DPN by counteracting multiple risk factors including mitochondrial dysfunction, oxidative stress, and inflammation, and DW14006 has been highlighted as a potential leading compound in the treatment of DPN.
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