DISPLACEMENT OF INSULIN-LIKE GROWTH-FACTORS FROM THEIR BINDING-PROTEINS AS A POTENTIAL TREATMENT FOR STROKE

Insulin-like growth factors I and II (IGF-I and IGF-Ii) play an import ant role in normal growth and brain development and protect brain cell s from several forms of injury The effects of IGFs are mediated by typ e-I and type-ii receptors and modulated by potentially six specific bi nding proteins that form high-affinity complexes with IGFs in blood an d cerebrospinal fluid (CSF) and under most circumstances inactivate th em. Because brain injury is commonly associated with increases in IGFs and their associated binding proteins, we hypothesized that displacem ent of this large ''pool'' of endogenous IGF from the binding proteins would elevate ''free'' IGF levels to elicit neuroprotective effects c omparable to those produced by administration of exogenous IGF. A huma n IGF-I analog [(Leu(24,59,60), Ala(31))hIGF-I] with high affinity to IGF-binding proteins (K-i = 0.3-3.9 nM) and no biological activity at the IGF receptors (K-i = > 10,000 nM) increased the levels of ''free, bioavailable'' IGF-I in the CSF. Intracerebroventricular administratio n of this analog up to Ih after an ischemic insult to the rat brain ha d a potent neuroprotective action comparable to IGF-I, This novel stra tegy for increasing ''free'' IGF levels in the brain may be useful for the treatment of stroke and other neurodegenerative diseases.