Activation of SIRT1 by silibinin improved mitochondrial health and alleviated the oxidative damage in experimental diabetic neuropathy and high glucose-mediated neurotoxicity

Abstract

Background

Silibinin (SBN), a sirtuin 1 (SIRT1) activator, has been evaluated for its anti-inflammatory activity in many inflammatory diseases. However, its role in diabetes-induced peripheral neuropathy (DPN) remains unknown. The SIRT1 activation convalesces nerve functions by improving mitochondrial biogenesis and mitophagy.

Methods

DPN was induced by streptozotocin (STZ) at a dose of 55 mg/kg, i.p. in the male SD rats whereas neurotoxicity was induced in Neuro2A cells by 30 mM (high glucose) glucose. Neurobehavioural (nerve conduction velocity and nerve blood flow) western blot, immunohistochemistry, and immunocytochemistry were performed to evaluate the protein expression and their cellular localisation.

Results

Two-week SBN treatment improved neurobehavioural symptoms, SIRT1, PGC-1α, and TFAM expression in the sciatic nerve and HG insulted N2A cells. It has also maintained the mitophagy by up-regulating PARL, PINK1, PGAM5, LC3 level and provided antioxidant defence by upregulating Nrf2.

Conclusion

SBN has shown neuroprotective potential in DPN through SIRT1 activation and antioxidant mechanism.

Keywords:

• Silibinin
• mitochondrial protease
• SIRT1
• Nrf2
• mitochondrial biogenesis

Acknowledgements

The authors sincerely thank Dr. Chandra Shekhar Sriram for proofreading this manuscript.

Ethical approval

This article does not contain any studies with human participants performed by any of the authors. All applicable international, national, and/or institutional guidelines for the care and use of animals were followed. All procedures performed in studies involving animals were by the ethical standards of the institution at which the studies were conducted (Institutional Animal Ethics Committee (IAEC)—NIPER Hyderabad, protocol no. NIPER/11/2019/PC/354).

Author contributions

Mr. Islauddin Khan (Department of Pharmacology and Toxicology, NIPER-Hyderabad, Telangana 500037, India) conceptualised and performed all the in vitro and animal studies, analysed the data, prepared figures, and wrote the manuscript; Ms. Kumari Preeti (Department of Pharmacology and Toxicology, NIPER-Hyderabad, Telangana 500037, India) helped in performing experiments, analysing, and evaluating data, and reviewing the manuscript; Dr. Rahul Kumar (Department of Pharmacology and Toxicology, NIPER-Hyderabad, Telangana 500037, India) also helped in performed studies, evaluated data and reviewed manuscript; Dr. Dharmendra Kumar Khatri (Department of Pharmacology and Toxicology, NIPER-Hyderabad, Telangana 500037, India), contributed to study conception and designing, evaluating data and reviewing the manuscript. Dr. Shashi Bala Singh (Department of Pharmacology and Toxicology, NIPER-Hyderabad, Telangana 500037, India) contributed to project conceptualisation, designing studies, evaluating data, and reviewing the manuscript.

Disclosure statement

The authors declare that there are no conflicts of interest.

Data availability statement

The data are available on request from the corresponding author upon reasonable request.

Additional information

Funding

Authors would like to acknowledge the financial support provided by the (Science and Engineering Research Board- Department of Science and Technology (SERB-DST) and Department of Pharmaceuticals, Ministry of Chemicals and Fertilizers, Government of India for carrying out this work.