nbi-31772 and Disease-Models--Animal

An unmet challenge of spinal cord injury research is the identification of mechanisms that promote regeneration of corticospinal motor axons. Recently it was reported that IGF-I promotes corticospinal axon growth during nervous system development. We therefore investigated whether IGF-I also promotes regeneration or survival of adult lesioned corticospinal neurons. Adult Fischer 344 rats underwent C3 dorsal column transections followed by grafts of IGF-I-secreting marrow stromal cell grafts into the lesion cavity. IGF-I secreting cell grafts promoted growth of raphespinal and cerulospinal axons, but not corticospinal axons, into the lesion/graft site. We then examined whether IGF-I-secreting cell grafts promote corticospinal motor neuron survival or axon growth in a subcortical axotomy model. IGF-I expression coupled with infusion of the IGF binding protein inhibitor NBI-31772 significantly prevented corticospinal motor neuron death (93% cell survival compared to 49% in controls, P<0.05), but did not promote corticospinal axon regeneration. Coincident with observed effects of IGF-I on corticospinal survival but not growth, expression of IGF-I receptors was restricted to the somal compartment and not the axon of adult corticospinal motor neurons. Thus, whereas IGF-I influences corticospinal axonal growth during development, its application to sites of adult spinal cord injury or subcortical axotomy fails to promote corticospinal axonal regeneration under conditions that are sufficient to prevent corticospinal cell death and promote the growth of other supraspinal axons. We conclude that developmental patterns of growth factor responsiveness are not simply recapitulated after adult injury, potentially due to post-natal shifts in patterns of IGF-I receptor expression.

Topics: Animals; Animals, Newborn; Bone Marrow Cells; Catechols; Cell Survival; Cells, Cultured; Cholera Toxin; Disease Models, Animal; Enzyme-Linked Immunosorbent Assay; Female; Gene Transfer Techniques; Genetic Therapy; Glial Fibrillary Acidic Protein; Insulin-Like Growth Factor I; Isoquinolines; Nerve Regeneration; Neurons; Pyramidal Tracts; Rats; Rats, Inbred F344; Spinal Cord Injuries; Transfection; Tyrosine 3-Monooxygenase

The present studies were conducted to determine if increasing central levels of the neurotrophic factor insulin-like growth factor-1 (IGF-I) either directly or indirectly produces anxiolytic and antidepressant-like effects in the mouse. Central levels of IGF-I can be increased directly, by administering IGF-I, or indirectly by blocking the insulin-like growth factor binding proteins (IGFBPs). The IGFBP family has the unique ability to regulate IGF-I levels by sequestering IGF-I into an inactive complex. Therefore, an IGFBP inhibitor increases the level of IGF-I available to bind to its receptor. Intracerebroventricular (icv) administration of the nonspecific IGFBP inhibitor NBI-31772 (10-30 microg) increases the number of punished crossings in the four-plate test and NBI-31772 (0.3-10 microg) increases time spent in the open quadrant of the elevated zero maze (EZM), indicative of anxiolytic-like effects. NBI-31772 (3-30 microg) also decreases immobility time in the tail suspension test, indicative of antidepressant-like effects. Similarly, icv administration of IGF-I (0.1 microg) produces anxiolytic-like effects in the four-plate test and IGF-1 (0.3-1 microg) produces anxiolytic-like effects in the EZM. IGF-I (10 microg) also produces antidepressant-like effects in the tail suspension test. Coadministration of the IGF-I receptor antagonist JB1 with NBI-31772 or IGF-I blocks the anxiolytic-like and antidepressant-like effects of these compounds. These results suggest that NBI-31772 produces behavioral effects by increasing levels of IGF-I that in turn activate the IGF-I receptor. The present studies demonstrate that an IGFBP inhibitor mimics the behavioral effects of IGF-I and that IGFBP inhibition may represent a novel mechanism by which to increase IGF-I to treat depression and anxiety.

Topics: Analysis of Variance; Animals; Antidepressive Agents; Anxiety; Avoidance Learning; Behavior, Animal; Catechols; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Interactions; Enzyme Inhibitors; Gene Expression Regulation; Hindlimb Suspension; Injections, Intraventricular; Insulin-Like Growth Factor Binding Proteins; Insulin-Like Growth Factor I; Isoquinolines; Male; Mice; Motor Activity