INSULIN-LIKE GROWTH-FACTORS - PUTATIVE MUSCLE-DERIVED TROPHIC AGENTS THAT PROMOTE MOTONEURON SURVIVAL

Treatment of chick embryos in ovo with IGF-I during the period of norm al, developmentally regulated neuronal death (embryonic days 5-10) res ulted in a dose-dependent rescue of a significant number of lumbar mot oneurons from degeneration and death. IGF-II and two variants of IGF-I with reduced affinity for IGF binding proteins, des(1-3) IGF-I and lo ng R(3) IGF-I, also elicited enhanced survival of motoneurons equal to that seen in IGF-I-treated embryos. IGF-I did not enhance mitogenic a ctivity in motoneuronal populations when applied to embryos during the period of normal neuronal proliferation (E2-5). Treatment of embryos with IGF-I also reduced two types of injury-induced neuronal death. Fo llowing either deafferentation or axotomy, treatment of embryos with I GF-I rescued approximately 75% and 50%, respectively, of the motoneuro ns that die in control embryos as a result of these procedures. Consis tent with the survival-promoting activity on motoneurons in ovo, IGF-I , -II, and des (1-3) IGF-I elevated choline acetyltransferase activity in embryonic rat spinal cord cultures, with des (1-3) IGF-I demonstra ting 2.5 times greater potency that did IGF-I. A single addition of IG F-I at culture initiation resulted in the maintenance of 80% of the in itial ChAT activity in untreated control cultures fell to 9%. In summa ry, these results demonstrate clear motoneuronal trophic activity for the IGFs. These findings, together with previous reports that IGFs are synthesized in muscle and may participate in motoneuron axonal regene ration and sprouting, indicate that these growth factors may have an i mportant role in motoneuron development, maintenance, and recovery fro m injury. (C) 1993 John Wiley & Sons, Inc.