DW14006 as a Direct AMPKα Activator Ameliorates Diabetic Peripheral Neuropathy in Mice
Xu Xu1, Wei Wang2,3, Zhengyu Wang4
1Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, China.
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-[2'-hydroxy-(1,1'-biphenyl)-4-yl]-2-oxo-1,2-dihydroquinolin-3-yl)phenyl]acetic acid) as a direct AMPKα 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 AMPKα, which has been verified by assay against the STZ-induced diabetic mice injected with adeno-associated virus 8-AMPKα-RNAi. To our knowledge, our work might be the first report on the amelioration of the direct AMPKα 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.
Insights
A novel compound, DW14006, directly activates AMP-activated protein kinase alpha (AMPKα) to effectively treat diabetic peripheral neuropathy (DPN). This treatment improves nerve function by reducing oxidative stress and inflammation in diabetic mice.
Area of Science:
- Biochemistry
- Neuroscience
- Pharmacology
Background:
- Diabetic peripheral neuropathy (DPN) is a significant complication of diabetes.
- AMP-activated protein kinase (AMPK) and mitochondrial function are crucial in DPN pathogenesis.
- Oxidative stress and inflammation contribute to DPN development.
Purpose of the Study:
- To investigate the therapeutic potential of DW14006, a direct AMPKα activator, for diabetic peripheral neuropathy (DPN).
- To elucidate the underlying mechanisms by which DW14006 ameliorates DPN in preclinical models.
Main Methods:
- Administration of DW14006 to streptozotocin (STZ)-induced type 1 and BKS db/db type 2 diabetic mice.
- Assessment of neurological function, neurite outgrowth, mitochondrial bioenergetics, oxidative stress, and inflammation.
- Validation using AMPKα-RNAi in STZ-induced diabetic mice.
Main Results:
- DW14006 significantly ameliorated DPN in both type 1 and type 2 diabetic mouse models.
- DW14006 enhanced neurite outgrowth and improved neurological function in diabetic mice.
- Treatment with DW14006 improved mitochondrial function and reduced oxidative stress and inflammation by targeting AMPKα.
Conclusions:
- DW14006, a direct AMPKα activator, demonstrates significant therapeutic potential for DPN.
- The compound counteracts key DPN risk factors including mitochondrial dysfunction, oxidative stress, and inflammation.
- DW14006 represents a promising leading compound for DPN treatment development.
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