KU-596 decreases mitochondrial superoxide and improves bioenergetics following downregulation of manganese superoxide dismutase in diabetic sensory neurons

You, Zhenyuan; Zhang, Zheng; Blagg, Brian S. J.; Dobrowsky, Rick T.

doi:10.1016/j.expneurol.2018.12.006

Cited by 7 publications

(16 citation statements)

References 40 publications

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“…Weight was evaluated every week. Animals that exhibited blood glucose levels > 16.7 mmol/L within 1 week after the completion of STZ injection were considered diabetic and were included in the study; these animals showed progression to neuropathy-like symptoms and were tested behaviourally after 6 weeks [29,30].…”

Section: Animals and Treatmentmentioning

confidence: 99%

Neuroprotective effect of diosgenin in a mouse model of diabetic peripheral neuropathy involves the Nrf2/HO-1 pathway

Jin-hong

Tian

et al. 2020

BMC Complement Med Ther

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Background: Diabetic peripheral neuropathy (DPN) is one of the most common chronic complications of diabetes. Diosgenin is a natural steroidal saponin with a variety of beneficial effects, including antidiabetic effects, and is a raw material for the synthesis of carrier hormones. In our study, we aimed to assess the antioxidant effects of diosgenin in diabetic mice. Methods: Male C57 mice were fed a high-fat diet for 8 weeks and intraperitoneally injected with streptozotocin (STZ) at a dose of 100 mg/kg for 2 consecutive days. Eligible mice were divided into the normal control group (CON), diabetic group (DM), low-dose diosgenin (50 mg/kg) group (DIO50) and high-dose diosgenin (100 mg/kg) group (DIO100). Treatment was started 6 weeks after the induction of diabetes by STZ and continued for 8 weeks. Blood sugar and body weight were monitored dynamically. The behavioural effects of diosgenin were detected by a hot tail immersion test and paw tactile responses. HE staining was used to evaluate edema and degeneration of the sciatic nerve. The levels of SOD, MDA and GPx were tested according to the instructions of the respective kits. The levels of Nrf2, HO-1 and NQO1 were detected by immunofluorescence and Western blotting. Statistical analysis was performed using SPSS, and P < 0.05 was considered statistically significant. Results: Diosgenin decreased the blood glucose levels and increased the body weight of diabetic mice. There was a significant increase in the tail withdrawal latency of diabetic animals, and mechanical hyperalgesia was significantly alleviated after diosgenin treatment. Histopathological micrographs of HE-stained sciatic nerves showed improvement after diosgenin treatment. Diosgenin attenuated the level of MDA but increased the activities of SOD and GPx. Diosgenin increased the expression of Nrf2, HO-1 and NQO1. Conclusions: Our results demonstrate that diosgenin can ameliorate behavioural and morphological changes in DPN by reducing oxidative stress. The Nrf2/HO-1 signalling pathway was involved in its neuroprotective effects.

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Section: Animals and Treatmentmentioning

confidence: 99%

Neuroprotective effect of diosgenin in a mouse model of diabetic peripheral neuropathy involves the Nrf2/HO-1 pathway

Jin-hong

Tian

et al. 2020

BMC Complement Med Ther

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“…We have shown that 8 weeks of KU-596 therapy reversed a pre-existing mechanical and thermal hypoalgesia, increased nerve conduction velocity, and improved deficits in mtBE that develop by 16 weeks of diabetes in C57Bl/6 mice. , To assess the effect of diabetes and KU-596 treatment on mitophagy, male and female 6–8 week-old MQC mice were rendered diabetic with two intraperitoneal injections of 100 mg/kg streptozotocin (STZ) given on consecutive days. After 8 weeks of diabetes, mice were administered 1 mg/kg KU-596 or Captisol (drug vehicle) by daily oral gavage for an additional 8 weeks.…”

Section: Resultsmentioning

confidence: 99%

“…In contrast, the drug did not improve MRC and SRC in neurons from diabetic MQC × Hsp70 KO mice. We have previously observed that nondiabetic Hsp70 KO neurons treated with KU-596 had a higher MRC and SRC than vehicle-treated nondiabetic neurons . Thus, the drug may have some Hsp70-independent effects to improve mtBE in nondiabetic neurons, but improving mtBE in diabetic neurons requires Hsp70 …”

Section: Resultsmentioning

confidence: 99%

“…An increase in oxidative damage is thought to contribute to mitochondrial dysfunction in diabetic neurons, and using electron paramagnetic resonance spectroscopy, we observed an increase in mitochondrial superoxide production in diabetic neurons that was diminished with KU-596 treatment. However, the ability of KU-596 to improve mtBE was not solely dependent on decreasing mitochondrial superoxide . Oxidative stress and mitophagy are interrelated processes implicated in a wide range of pathological conditions involving high energy demanding tissues.…”

Section: Discussionmentioning

confidence: 96%

“…Novologues are proprietary small molecule neurotherapeutics whose chemical biology is directed at modulating the activity and expression of molecular chaperones, such as heat shock protein 90 (Hsp90) and Hsp70. Over the last 12 years, we have published robust and rigorous data showing that novologues improve metabolic and clinical indices of DPN. − KU-596 is a clinically advanced novologue (ChemSpider ID: 28665905) that binds to the C-terminal of Hsp90 to improve DPN in an Hsp70-dependent manner. , Moreover, improvement in physiologic measures of DPN by KU-596 correlate with enhancing mitochondrial bioenergetics (mtBE) and decreasing oxidative stress. , Although the efficacy of KU-596 in improving mtBE requires Hsp70, downstream mechanisms remain undefined.…”

Section: Introductionmentioning

confidence: 99%

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Novologue Therapy Requires Heat Shock Protein 70 and Thioredoxin-Interacting Protein to Improve Mitochondrial Bioenergetics and Decrease Mitophagy in Diabetic Sensory Neurons

Rodriguez

Kaur

Nolte

et al. 2021

ACS Chem. Neurosci.

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Diabetic peripheral neuropathy (DPN) is a complication of diabetes whose pathophysiology is linked to altered mitochondrial bioenergetics (mtBE). KU-596 is a small molecule neurotherapeutic that reverses symptoms of DPN, improves sensory neuron mtBE, and decreases the pro-oxidant protein, thioredoxin-interacting protein (Txnip) in a heat shock protein 70 (Hsp70)-dependent manner. However, the mechanism by which KU-596 improves mtBE and the role of Txnip in drug efficacy remains unknown. Mitophagy is a quality-control mechanism that selectively targets damaged mitochondria for degradation. The goal of this study was to determine if KU-596 therapy improved DPN, mtBE, and mitophagy in an Hsp70-and Txnip-dependent manner. Mito-QC (MQC) mice express a mitochondrially targeted mCherry-GFP fusion protein that enables visualizing mitophagy. Diabetic MQC, MQC × Hsp70 knockout (KO), and MQC × Txnip KO mice developed sensory and nerve conduction dysfunctions consistent with the onset of DPN. KU-596 therapy improved these measures, and this was dependent on Hsp70 but not Txnip. In MQC mice, diabetes decreased mtBE and increased mitophagy and KU-596 treatment reversed these effects. In contrast, KU-596 was unable to improve mtBE and decrease mitophagy in MQC × Hsp70 and MQC × Txnip KO mice. These data suggest that Txnip is not necessary for the development of the sensory symptoms and mitochondrial dysfunction induced by diabetes. KU-596 therapy may improve mitochondrial tolerance to diabetic stress to decrease mitophagic clearance in an Hsp70-and Txnip-dependent manner.

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Neurobiological Opportunities in Diabetic Polyneuropathy

2021

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This review highlights a selection of potential translational directions for the treatment of diabetic polyneuropathy (DPN) currently irreversible and without approved interventions beyond pain management. The list does not include all diabetic targets that have been generated over several decades of research but focuses on newer work. The emphasis is firstly on approaches that support the viability and growth of peripheral neurons and their ability to withstand a barrage of diabetic alterations. We include a section describing Schwann cell targets and finally how mitochondrial damage has been a common element in discussing neuropathic damage. Most of the molecules and pathways described here have not yet reached clinical trials, but many trials have been negative to date. Nonetheless, these failures clear the pathway for new thoughts over reversing DPN.

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KU-596 decreases mitochondrial superoxide and improves bioenergetics following downregulation of manganese superoxide dismutase in diabetic sensory neurons

Cited by 7 publications

References 40 publications

Neuroprotective effect of diosgenin in a mouse model of diabetic peripheral neuropathy involves the Nrf2/HO-1 pathway

Neuroprotective effect of diosgenin in a mouse model of diabetic peripheral neuropathy involves the Nrf2/HO-1 pathway

Novologue Therapy Requires Heat Shock Protein 70 and Thioredoxin-Interacting Protein to Improve Mitochondrial Bioenergetics and Decrease Mitophagy in Diabetic Sensory Neurons

Neurobiological Opportunities in Diabetic Polyneuropathy

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