Isoliquiritigenin reduces oxidative damage and alleviates mitochondrial impairment by SIRT1 activation in experimental diabetic neuropathy

J Nutr Biochem. 2017 Sep;47:41-52. doi: 10.1016/j.jnutbio.2017.05.001. Epub 2017 May 11.

Abstract

Sirtuin (SIRT1) inactivation underlies the pathogenesis of insulin resistance and hyperglycaemia-associated vascular complications, but its role in diabetic neuropathy (DN) has not been yet explored. We have evaluated hyperglycaemia-induced alteration of SIRT1 signalling and the effect of isoliquiritigenin (ILQ) on SIRT1-directed AMP kinase (AMPK) and peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) signalling in peripheral nerves of streptozotocin (STZ) (55 mg/kg, ip)-induced diabetic rats and in high glucose (30 mM)-exposed neuro2a (N2A) cells. Diabetic rats and high glucose-exposed N2A cells showed reduction in SIRT1 expression with consequent decline in mitochondrial biogenesis and autophagy. ILQ (10 & 20 mg/kg, po) administration to diabetic rats for 2 weeks and exposure to glucose-insulted N2A cells resulted in significant SIRT1 activation with concurrent increase in mitochondrial biogenesis and autophagy. ILQ administration also enhanced NAD+/NADH ratio in peripheral sciatic nerves which explains its possible SIRT1 modulatory effect. Functional and behavioural studies show beneficial effect of ILQ as it alleviated nerve conduction and nerve blood flow deficits in diabetic rats along with improvement in behavioural parameters (hyperalgesia and allodynia). ILQ treatment to N2A cells reduced high glucose-driven ROS production and mitochondrial membrane depolarization. Further, ILQ-mediated SIRT1 activation facilitated the Nrf2-directed antioxidant signalling. Overall, results from this study suggest that SIRT1 activation by ILQ mimic effects of calorie restriction, that is, PGC-1α-mediated mitochondrial biogenesis, FOXO3a mediated stress resistance and AMPK mediated autophagy effects to counteract the multiple manifestations in experimental DN.

Keywords: AMPK; Autophagy; Mitochondriogenesis; NAD(+); PGC-1α; SIRT1.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antioxidants / metabolism
  • Antioxidants / therapeutic use*
  • Autophagy
  • Blood Glucose / analysis
  • Cell Line, Tumor
  • Chalcones / metabolism
  • Chalcones / therapeutic use*
  • Diabetic Neuropathies / blood
  • Diabetic Neuropathies / diet therapy*
  • Diabetic Neuropathies / metabolism
  • Diabetic Neuropathies / pathology
  • Enzyme Activation
  • Male
  • Membrane Potential, Mitochondrial
  • Mice
  • Mitochondrial Dynamics
  • Nerve Tissue Proteins / agonists
  • Nerve Tissue Proteins / metabolism
  • Neural Conduction
  • Neurons / metabolism*
  • Neurons / pathology
  • Organelle Biogenesis
  • Oxidative Stress*
  • Peripheral Nerves / blood supply
  • Peripheral Nerves / metabolism*
  • Peripheral Nerves / pathology
  • Rats, Sprague-Dawley
  • Sciatic Nerve
  • Signal Transduction
  • Sirtuin 1 / chemistry
  • Sirtuin 1 / metabolism*

Substances

  • Antioxidants
  • Blood Glucose
  • Chalcones
  • Nerve Tissue Proteins
  • isoliquiritigenin
  • Sirtuin 1