Adenosine monophosphate-activated protein kinase modulation by berberine attenuates mitochondrial deficits and redox imbalance in experimental diabetic neuropathy

Neuropharmacology. 2018 Mar 15;131:256-270. doi: 10.1016/j.neuropharm.2017.12.029. Epub 2017 Dec 20.

Abstract

Adenosine monophosphate-activated protein kinase (AMPK) has been studied for its myriad metabolic and mitochondrial benefits in several chronic diseases. Recent studies have uncovered its therapeutic potential against mitochondrial dysfunction in cultured dorsal root ganglion (DRG) neurons isolated from streptozotocin (STZ) induced diabetic rats. The present study is aimed at evaluating the pharmacological efficacy of berberine (BRB), a natural AMPK activator against experimental diabetic neuropathy (DN) phenotype developed in STZ (55 mg/kg, i.p.) induced diabetic rats and neurotoxicity in high-glucose (30 mM) stimulated neuro 2a (N2A) cells. Diabetic-rats have shown reduced expression of p-AMPK (Thr 172) in sciatic nerves with a consequent reduction in mitochondrial biogenesis and autophagy. BRB (50 & 100 mg/kg, po) administration to diabetic rats for 2-weeks rescued mitochondrial functional deficits and autophagy impairment by increasing the p-AMPK expression. BRB administration also augmented the NEF-2 related factor 2 (Nrf2) mediated endogenous antioxidant defence systems to restrain neuronal damage and neuroinflammation. These effects after BRB administration resulted in enhanced conduction velocity, improved nerve blood flow and attenuated hyperalgesia. Similarly, BRB exposure (5 & 10 μM) to N2A cells attenuated high glucose induced ROS generation, mitochondrial membrane depolarization through the promotion of Nrf2 mediated antioxidant defence systems. BRB exposure augmented peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) mediated mitochondrial biogenesis in neuronal cells. Results from this study signify the importance of mitoprotection conferred by BRB in DN and can be used as a preliminary basis for further molecular exploration.

Keywords: AMPK; Autophagy; Berberine; Diabetic neuropathy; Mitochondrial biogenesis; Oxidative stress.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenylate Kinase / metabolism*
  • Animals
  • Autophagy / drug effects
  • Autophagy / physiology
  • Berberine / pharmacology*
  • Cell Line
  • Diabetes Mellitus, Experimental / drug therapy
  • Diabetes Mellitus, Experimental / metabolism
  • Diabetes Mellitus, Experimental / pathology
  • Diabetic Neuropathies / drug therapy*
  • Diabetic Neuropathies / metabolism
  • Diabetic Neuropathies / pathology
  • Dose-Response Relationship, Drug
  • Glucose / toxicity
  • Hypoglycemic Agents / pharmacology*
  • Male
  • Mice
  • Mitochondria / drug effects*
  • Mitochondria / metabolism
  • Mitochondria / pathology
  • Neuroprotective Agents / pharmacology*
  • Organelle Biogenesis
  • Oxidation-Reduction / drug effects
  • Rats, Sprague-Dawley
  • Sciatic Nerve / drug effects
  • Sciatic Nerve / metabolism
  • Sciatic Nerve / pathology

Substances

  • Hypoglycemic Agents
  • Neuroprotective Agents
  • Berberine
  • Adenylate Kinase
  • Glucose