DW14006 as a Direct AMPKα Activator Ameliorates Diabetic Peripheral Neuropathy in Mice

Abstract

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.

Bone transport induces the release of factors with multi-tissue regenerative potential for diabetic wound healing in rats and patients

“…Peripheral neuropathy is one of the common causes of DFU. To determine whether BT-sEVs have the potential to improve peripheral neuropathy in diabetic mice, we selected 8-week-old db/db mice 19 and injected normal saline, sham-sEVs, or BT-sEVs (100 μg/2 days) into their tail veins. After 2 weeks of treatment, the dorsal root ganglion (DRG) neurons of each group of db/db mice were cultured in vitro .…”

A Mitochondrial Nanoguard Modulates Redox Homeostasis and Bioenergy Metabolism in Diabetic Peripheral Neuropathy

“…In an early stage of DPN, the distal epidermal nerve (foot pad nerve) is frequently affected, manifesting as decreased thermal and mechanical sensation. , The Von-Frey test was used to measure the mechanical sensitivity (Figure B). db/db mice exhibited a higher pain threshold, for about 200% compared to the ctrl group at 10 weeks old.…”

“…Diabetic peripheral neuropathy (DPN) is the most frequently seen complication of diabetes, and it adversely affects all peripheral nerves including sensory fibers, motor neurons, and the autonomic nervous system. , It should be spotlighted that two-thirds of all diabetic patients experience DPN, most often those with type 2 diabetes mellitus (T2DM), which is ascribed to decreased pancreatic β-cell function and insulin insensitivity. − Patients with DPN often experience symmetrical limb symptoms, such as pain, numbness, and nociceptive abnormalities, known as socking glove neuropathy . Worse still, DPN is the leading cause of refractory ulcers and amputation worldwide, increasing the risks of depression and cardiovascular problems. − Despite the enormous burdens that DPN imposes on patients and society, there are no Food and Drug Administration (FDA)-approved drugs for its treatment, apart from blood glucose management.…”

Sudomotor dysfunction in diabetic peripheral neuropathy (DPN) and its testing modalities: A literature review

“…Upregulation of AMPK has been shown to exert a protective effect by inhibiting cell death, inflammation, and oxidative stress. Several studies also found improved mitochondrial function, decreased inflammatory agents, and declining glucose levels upon activation of the AMPK pathway [ 57 , 58 ]. On the other hand, AMPK downregulation, often induced by chronic hyperglycemia, has been shown to result in mitochondrial damage, a prominent finding in diabetic neuropathy.…”