Intranasally administered IGF-1 inhibits spreading depression in vivo

Brain Res. 2017 Dec 15;1677:47-57. doi: 10.1016/j.brainres.2017.09.022. Epub 2017 Sep 23.

Abstract

Spreading depression (SD) is a wave of cellular depolarization that travels slowly through susceptible gray matter brain areas. SD is the most likely cause of migraine aura and perhaps migraine pain, and is a well-accepted animal model of migraine. Identification of therapeutics that can prevent SD may have clinical relevance toward migraine treatment. Here we show that insulin-like growth factor-1 (IGF-1) significantly inhibited neocortical SD in vivo after intranasal delivery to rats. A single dose of IGF-1 inhibited SD within an hour, and continued to protect for at least seven days thereafter. A two-week course of IGF-1, administered every third day, further decreased SD susceptibility and showed no aberrant effects on glial activation, nasal mucosa, or serum markers of toxicity. SD begets SD in vitro by mechanisms that involve microglial activation. We add to this relationship by showing that recurrent SD in vivo increased susceptibility to subsequent SD, and that intervention with IGF-1 significantly interrupted this pathology. These findings support nasal administration of IGF-1 as a novel intervention capable of mitigating SD susceptibility, and as a result, potentially migraine.

Keywords: Inflammation; Insulin-like growth factor-1; Microglia; Migraine; Neuroinflammation; Neurotherapeutics; Spreading depression.

MeSH terms

  • Administration, Intranasal
  • Animals
  • Cortical Spreading Depression / drug effects*
  • Cortical Spreading Depression / physiology
  • Humans
  • Insulin-Like Growth Factor I / administration & dosage*
  • Male
  • Nasal Mucosa / cytology
  • Nasal Mucosa / drug effects
  • Neocortex / cytology
  • Neocortex / drug effects*
  • Neocortex / physiology
  • Neuroglia / cytology
  • Neuroglia / drug effects
  • Neuroprotective Agents / administration & dosage*
  • Potassium Chloride
  • Random Allocation
  • Rats, Wistar

Substances

  • IGF1 protein, human
  • Neuroprotective Agents
  • Potassium Chloride
  • Insulin-Like Growth Factor I