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Berberine activates Nrf2 nuclear translocation and protects against oxidative damage via a phosphatidylinositol 3-kinase/Akt-dependent mechanism in NSC34 motor neuron-like cells

Eur J Pharm Sci. 2012 Aug 15;46(5):415-25. doi: 10.1016/j.ejps.2012.03.004. Epub 2012 Mar 24.

Abstract

Berberine (BBR) is a well-known anti-diabetic herbal medicine in Asia due to its beneficial effects on insulin sensitivity, glucose metabolism and glycolysis. Here, we identified the critical role of phosphatidylinositol 3-kinase (PI3K)/Akt involved BBR cellular defense mechanisms and first revealed the novel effect of BBR on nuclear factor (erythroid-derived 2)-related factor-2 (Nrf2)/heme oxygenase (HO)-1 induction in NSC34 motor neuron-like cells. BBR (0.1-10 nM) led to increasing insulin receptor expression, Akt phosphorylation and enhanced oxidant-sensitive Nrf2/HO-1 induction, which were blocked by a PI3K inhibitor, LY294002. In H(2)O(2)-treated cells, BBR significantly attenuated ROS production and increased cell viability, antioxidant defense (GSH and SOD) and oxidant-sensitive proteins (HO-1 and Nrf2), which also were blocked by LY294002. Furthermore, BBR improved mitochondrial function by increasing mitochondrial membrane potential and decreasing the oxygen consumption rate. BBR-induced anti-apoptotic function was demonstrated by increasing anti-apoptotic protein Bcl-2 and survival of motor neuron protein (SMN) and by decreasing apoptotic proteins (cytochrome c, Bax and caspase). These results suggest that BBR, which is active at nanomolar concentration, is a potential neuroprotective agent via PI3K/Akt-dependent cytoprotective and antioxidant pathways.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Active Transport, Cell Nucleus / drug effects
  • Animals
  • Antioxidants / pharmacology*
  • Apoptosis / drug effects
  • Berberine / pharmacology*
  • Cell Line, Tumor
  • Chromones / pharmacology
  • Cytoprotection
  • Dose-Response Relationship, Drug
  • Glutathione / metabolism
  • Heme Oxygenase-1 / metabolism
  • Hydrogen Peroxide / toxicity
  • Membrane Proteins / metabolism
  • Mice
  • Mitochondria / drug effects
  • Mitochondria / metabolism
  • Morpholines / pharmacology
  • Motor Neurons / drug effects*
  • Motor Neurons / enzymology
  • Motor Neurons / pathology
  • NF-E2-Related Factor 2 / metabolism*
  • Neuroprotective Agents / pharmacology*
  • Oxidants / toxicity
  • Oxidative Stress / drug effects*
  • Phosphatidylinositol 3-Kinase / metabolism*
  • Protein Kinase Inhibitors / pharmacology
  • Proto-Oncogene Proteins c-akt / metabolism*
  • Receptor, IGF Type 1 / drug effects
  • Receptor, IGF Type 1 / metabolism
  • Receptor, Insulin / drug effects
  • Receptor, Insulin / metabolism
  • Signal Transduction / drug effects
  • Superoxide Dismutase / metabolism

Substances

  • Antioxidants
  • Chromones
  • Membrane Proteins
  • Morpholines
  • NF-E2-Related Factor 2
  • Neuroprotective Agents
  • Nfe2l2 protein, mouse
  • Oxidants
  • Protein Kinase Inhibitors
  • Berberine
  • 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
  • Hydrogen Peroxide
  • Heme Oxygenase-1
  • Hmox1 protein, mouse
  • Superoxide Dismutase
  • Phosphatidylinositol 3-Kinase
  • Receptor, IGF Type 1
  • Receptor, Insulin
  • Proto-Oncogene Proteins c-akt
  • Glutathione