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

The blood-central nervous system-barrier (B-CNS-B) is widely considered a s ignificant impediment to the use of protein neurotrophic factors for the tr eatment of brain diseases and disorders. In this study, we tested the hypot hesis that systemic administration of insulin-like growth factor I (IGF-I) can ameliorate functional damage to the central nervous system. Intracister nal injection of g-hydroxydopamine (6-OHDA) normally results in loss of bot h the descending spinal cord noradrenergic (NA) fibers and the hindlimb wit hdrawal reflex. Ten minutes after 6-OHDA or solvent injection, 1 week durat ion osmotic minipumps containing IGF-I or vehicle were implanted subcutaneo usly in the mid-back of adult rats. Three weeks post-surgery, the maximum s timulus-evoked withdrawal force of the hindlimb was measured. This withdraw al 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 enlargeme nt containing the motoneurons mediating the hindlimb reflexes. The interspe rsed NA axons and their bead-like varicosities were stained with an anti-do pamine-beta-hydroxylase antibody. The mean number of NA varicosities per un it area in the ventral horn was profoundly reduced in lesioned vs. nonlesio ned rats (P < 0.0002), but significant numbers (51%) were retained in lesio ned 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. (C) 1999 Academic Press.