Peripherally administered insulin-like growth factor-I preserves hindlimb reflex and spinal cord noradrenergic circuitry following a central nervous system lesion in rats

Exp Neurol. 1999 Sep;159(1):114-23. doi: 10.1006/exnr.1999.7143.


The blood-central nervous system-barrier (B-CNS-B) is widely considered a significant impediment to the use of protein neurotrophic factors for the treatment of brain diseases and disorders. In this study, we tested the hypothesis that systemic administration of insulin-like growth factor I (IGF-I) can ameliorate functional damage to the central nervous system. Intracisternal injection of 6-hydroxydopamine (6-OHDA) normally results in loss of both the descending spinal cord noradrenergic (NA) fibers and the hindlimb withdrawal reflex. Ten minutes after 6-OHDA or solvent injection, 1 week duration osmotic minipumps containing IGF-I or vehicle were implanted subcutaneously in the mid-back of adult rats. Three weeks post-surgery, the maximum stimulus-evoked withdrawal force of the hindlimb was measured. This withdrawal reflex was significantly reduced in 6-OHDA lesioned vs. nonlesioned rats (P <.0002). The mean maximum reflex force was significantly larger in IGF-I vs. vehicle-treated lesioned rats (P < 0.008). Following reflex testing, serial sections of the spinal cord were taken through the lumbar enlargement containing the motoneurons mediating the hindlimb reflexes. The interspersed NA axons and their bead-like varicosities were stained with an anti-dopamine-beta-hydroxylase antibody. The mean number of NA varicosities per unit area in the ventral horn was profoundly reduced in lesioned vs. nonlesioned rats (P < 0.0002), but significant numbers (51%) were retained in lesioned rats treated with IGF-I vs. vehicle (P < 0.02). These data suggest that blood-borne IGF-I preserves both reflex function and spinal cord circuitry following injury to NA axons and that the blood-CNS fluid barriers may not be an impediment for IGF-I entry into the CNS.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Axons / chemistry
  • Axons / enzymology
  • Denervation
  • Dopamine beta-Hydroxylase / analysis
  • Hindlimb
  • Injections, Subcutaneous
  • Insulin-Like Growth Factor I / pharmacology*
  • Locus Coeruleus / chemistry
  • Locus Coeruleus / cytology
  • Locus Coeruleus / physiology
  • Male
  • Motor Neurons / chemistry
  • Motor Neurons / enzymology
  • Motor Neurons / ultrastructure
  • Norepinephrine / physiology*
  • Oxidopamine
  • Rats
  • Rats, Sprague-Dawley
  • Reflex / drug effects*
  • Somatomedins / physiology
  • Spinal Cord / chemistry
  • Spinal Cord / cytology
  • Spinal Cord Injuries / drug therapy*
  • Sympatholytics


  • Somatomedins
  • Sympatholytics
  • Insulin-Like Growth Factor I
  • Oxidopamine
  • Dopamine beta-Hydroxylase
  • Norepinephrine