Insulin-like growth factor-1 abrogates microglial oxidative stress and TNF-α responses to spreading depression

J Neurochem. 2013 Sep;126(5):662-72. doi: 10.1111/jnc.12267. Epub 2013 Apr 30.


Spreading depression (SD), the most likely cause of migraine aura and perhaps migraine, occurs with increased oxidative stress (OS). SD increases reactive oxygen species (ROS), and ROS, in turn, can signal to increase neuronal excitability,which includes increased SD susceptibility. SD also elevates tumor necrosis factor-α (TNF-α), which increases neuronal excitability. Accordingly, we probed for the cellular origin of OS from SD and its relationship to TNF-α, which might promote SD, using rat hippocampal slice cultures. We observed significantly increased OS from SD in astrocytes and microglia but not in neurons or oligodendrocytes. Since insulin-like growth factor-1 (IGF-1) mitigates OS from SD, we determined the cell types responsible for this effect. We found that IGF-1 significantly decreased microglial but not astrocytic OS from SD. We also show that IGF-1 abrogated the SD-induced TNF-α increase. Furthermore, TNF-α application increased microglial but not astrocytic OS, an effect abrogated by IGF-1. Next,we showed that SD increased SD susceptibility, and does so via TNF-α. This work suggests that microglia promote SD via increased and interrelated ROS and TNF-α signaling. Thus, IGF-1 mitigation of microglial ROS and TNF-α responses maybe targets for novel therapeutics development to prevent SD, and perhaps migraine.

Keywords: IGF-1; microglia; migraine; oxidative stress; reactive oxygen species; spreading depression.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cortical Spreading Depression / drug effects*
  • Electrophysiological Phenomena
  • Female
  • Image Processing, Computer-Assisted
  • Immunohistochemistry
  • Insulin-Like Growth Factor I / pharmacology*
  • Microglia / drug effects*
  • Microscopy, Confocal
  • Neurons / drug effects
  • Oligodendroglia / drug effects
  • Organ Culture Techniques
  • Oxidative Stress / drug effects*
  • Pregnancy
  • Rats
  • Rats, Wistar
  • Reactive Oxygen Species
  • Receptors, Tumor Necrosis Factor, Type I / genetics
  • Receptors, Tumor Necrosis Factor, Type I / metabolism
  • Tissue Fixation
  • Tumor Necrosis Factor-alpha / metabolism*
  • Tumor Necrosis Factor-alpha / physiology


  • Reactive Oxygen Species
  • Receptors, Tumor Necrosis Factor, Type I
  • Tumor Necrosis Factor-alpha
  • Insulin-Like Growth Factor I