Insulin inhibits AMPA-induced neuronal damage via stimulation of protein kinase B (Akt)

J Neural Transm (Vienna). 2005 Feb;112(2):179-91. doi: 10.1007/s00702-004-0163-6. Epub 2004 Jun 21.

Abstract

We designed a series of experiments to explore the neuroprotective effects of insulin. Insulin significantly inhibited the alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA)-induced neuronal cell damage as evidenced by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium-bromide (MTT) assay. However, insulin had little affect on the AMPA-induced glial cell damage. To determine whether insulin inhibits AMPA-induced excitotoxicity, we performed grease-gap recording assays using rat brain slices. In these experiments, insulin also significantly inhibited AMPA-induced depolarization. Flow cytometry and DNA fragmentation assays showed that insulin inhibits AMPA-induced apoptosis and DNA fragmentation, respectively. Insulin stimulated protein kinase B (Akt) activity, whereas AMPA pretreatment did not alter the insulin-stimulated Akt activity. On the contrary, insulin blocked induction of SAPK/JNK, which AMPA stimulated. Taken together, these results suggest that insulin exerts neuroprotective effects by inhibiting AMPA-induced excitotoxicity and apoptosis, possibly by activating Akt and blocking SAPK/JNK.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Line
  • Dose-Response Relationship, Drug
  • Enzyme Activation / drug effects
  • Enzyme Activation / physiology
  • In Vitro Techniques
  • Insulin / pharmacology*
  • Insulin / therapeutic use
  • Male
  • Nerve Degeneration / drug therapy
  • Nerve Degeneration / metabolism
  • Nerve Degeneration / pathology
  • Neural Inhibition / drug effects*
  • Neural Inhibition / physiology
  • Neurons / drug effects*
  • Neurons / metabolism
  • Neurons / pathology
  • Neuroprotective Agents / pharmacology*
  • Neuroprotective Agents / therapeutic use
  • Protein Serine-Threonine Kinases / metabolism*
  • Protein Serine-Threonine Kinases / physiology
  • Proto-Oncogene Proteins / metabolism*
  • Proto-Oncogene Proteins / physiology
  • Proto-Oncogene Proteins c-akt
  • Rats
  • Rats, Sprague-Dawley
  • alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid / antagonists & inhibitors*
  • alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid / toxicity*

Substances

  • Insulin
  • Neuroprotective Agents
  • Proto-Oncogene Proteins
  • alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid
  • Akt1 protein, rat
  • Protein Serine-Threonine Kinases
  • Proto-Oncogene Proteins c-akt