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 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.
Pulford
B E
BE
Department of Biochemistry and Molecular Biology, Colorado State University, Fort Collins, Colorado, 80523, USA.
Whalen
L R
LR
Ishii
D N
DN
D000818:Animals; D001369:Axons / Q000737:chemistry / Q000201:enzymology; D003714:Denervation; D004299:Dopamine beta-Hydroxylase / Q000032:analysis; D006614:Hindlimb; D007279:Injections, Subcutaneous; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology*; D008125:Locus Coeruleus / Q000737:chemistry / Q000166:cytology / Q000502:physiology; D008297:Male; D009046:Motor Neurons / Q000737:chemistry / Q000201:enzymology / Q000648:ultrastructure; D009638:Norepinephrine / Q000502:physiology*; D016627:Oxidopamine; D051381:Rats; D017207:Rats, Sprague-Dawley; D012018:Reflex / Q000187:drug effects*; D013002:Somatomedins / Q000502:physiology; D013116:Spinal Cord / Q000737:chemistry / Q000166:cytology; D013119:Spinal Cord Injuries / Q000188:drug therapy*; D013565:Sympatholytics
D013002:Somatomedins; D013565:Sympatholytics; D007334:Insulin-Like Growth Factor I; D016627:Oxidopamine; D004299:Dopamine beta-Hydroxylase; D009638:Norepinephrine