Peripherally Administered Insulin-like Growth Factor-I Preserves Hindlimb Reflex and Spinal Cord Noradrenergic Circuitry Following a Central Nervous System Lesion in Rats

Abstract

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-β-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.