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Bardoxolone Methyl Ameliorates Hyperglycemia Induced Mitochondrial Dysfunction by Activating the keap1-Nrf2-ARE Pathway in Experimental Diabetic Neuropathy

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Abstract

Bardoxolone methyl (Bard), a nuclear factor erythroid 2-related factor 2 (Nrf2) activator regulates multiple oxidative and inflammatory diseases. However, the role of Bard in painful diabetic neuropathy (DN) remains unknown. Bard administration at two dose levels (15 & 30 mg/kg/day) to STZ (55 mg/kg, i.p) induced diabetic rats for last two weeks of eight week study significantly improved motor nerve conduction velocity (61.84 ± 1.9 vs. 38.57 ± 1.08 m/s), sensory nerve conduction velocity (66.86 ± 5.1 vs. 39.43 ± 3.3 m/s), nerve blood flow (86.28 ± 6.4 vs. 56.56 ± 1.62 PU), and intraepidermal nerve fiber density. Additionally, Bard treatment attenuated thermal and mechanical hyperalgesia in diabetic rats. Further molecular investigation on dorsal root ganglions (DRG) tissue isolated from L4-L6 regions of diabetic rats and High glucose (HG) exposed PC12 cells displayed decreased expression and transcriptional activity of Nrf2 which might have resulted in depleted antioxidant enzymes and mitochondrial chaperones. Bard treatment significantly reversed these effects in diabetic rats and also in HG exposed PC12 cells. Moreover, mitochondrial complex activities were diminished in DRG mitochondrial fractions of diabetic rats and mitochondrial isolates of HG exposed PC12 cells and Bard treatment significantly reversed these effects. Furthermore, Bard treatment significantly impeded the impact of hyperglycemic insults on mitochondrial membrane potential, ROS production and mitochondrial oxygen consumption rate (OCR) (Basal respiration, Maximal respiration, ATP production and spare respiratory capacity) in PC12 cells. Collectively our data suggests that Bard treatment to STZ induced diabetic rats robustly reduces DN which may be due to its effect on Keap1-Nrf2-ARE pathway and have contributed to improvement in mitochondrial function.

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Acknowledgements

Authors would like to acknowledge the financial support provided by the Department of Pharmaceuticals, Ministry of Chemicals and Fertilizers, Government of India for carrying out this work.

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  1. Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER)-Hyderabad, Bala Nagar, Hyderabad, TG-500037, India

    Anil Kumar Kalvala, Rahul Kumar, Bhoomika Sherkhane, Chayanika Gundu, Vijay Kumar Arruri & Ashutosh Kumar

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  1. Anil Kumar Kalvala
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Mr. Anil Kumar Kalvala (Department of Pharmacology and Toxicology, NIPER-HYDERABAD, Telangana, India - 500,037), Performed studies, evaluated data, prepared figures and wrote manuscript; Dr. Rahul Kumar (Department of Pharmacology and Toxicology, NIPER-HYDERABAD, Telangana, India - 500,037), Performed studies, evaluated data and reviewed manuscript; Ms. Bhoomika (Department of Pharmacology and Toxicology, NIPER-HYDERABAD, Telangana, India - 500,037), Performed studies, evaluated data and reviewed manuscript; Ms. Chayanika (Department of Pharmacology and Toxicology, NIPER-HYDERABAD, Telangana, India - 500,037), Performed studies, evaluated data and reviewed manuscript; Mr. Vijay Kumar (Department of Pharmacology and Toxicology, NIPER-HYDERABAD, Telangana, India - 500,037), Performed studies, evaluated data and reviewed manuscript; Dr. Ashutosh Kumar (Department of Pharmacology and Toxicology, NIPER-HYDERABAD, Balanagar, Telangana, India - 500,037), Designed, Performed studies, evaluated data and wrote manuscript.

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Kalvala, A.K., Kumar, R., Sherkhane, B. et al. Bardoxolone Methyl Ameliorates Hyperglycemia Induced Mitochondrial Dysfunction by Activating the keap1-Nrf2-ARE Pathway in Experimental Diabetic Neuropathy. Mol Neurobiol 57, 3616–3631 (2020). https://doi.org/10.1007/s12035-020-01989-0

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