SYSTEMIC ADMINISTRATION OF RHIGF-I ENHANCED REGENERATION AFTER SCIATIC-NERVE CRUSH IN MICE

Despite numerous reports suggesting that insulin-like growth factor-I (IGF-I) may be involved in the survival and regeneration of damaged ne urons in vitro and after local administration in vivo, there have been few studies on the effect of IGF-I administered systemically on regen eration of damaged nerves in vivo and the functional consequences of e nhanced regeneration. In an earlier study, recombinant human IGF-I (rh IGF-I) administered systemically enhanced the rate of regeneration aft er a sciatic crush as measured by the number of nerve fibers/muscle se ction. The purpose of this study was to follow up this finding by eval uating whether rhIGF-I administered peripherally enhances the rate of functional recovery. In this study following nerve injury, mice lost t he ability to grip a wire screen with their hind paws and to walk norm ally as indicated by a decrease in toe spread, internal toe spread and an increase in the angle between hind feet. The ability of injured mi ce treated with rhIGF-I to grip an inverted screen returned to control levels significantly faster than that of vehicle-treated mice (day 12 vs. day 15, respectively). Similarly, rhIGF-I treatment of injured mi ce resulted in toe spread, internal toe spread and angle values that w ere significantly better than that of vehicle-treated mice and returne d to control levels faster than vehicle-treated injured mice, There wa s a parallel loss of innervation after sciatic nerve crush as measured by a loss in choline acetyltransferase activity in the soleus and gas trocnemius muscles. Similarly, rhIGF-I treatment resulted in choline a cetyltransferase activity that was better than that of the injured/veh icle group. When rhIGF-I was evaluated over a broad range of doses (0. 1-30 mg/kg), all the doses of rhIGF-I resulted in a faster rate of fun ctional recovery than that of vehicle-treated injured mice with the do se of 1 mg/kg producing a maximal effect. The fact that doses of rhIGF -I greater than 1 mg/kg did not show an increased effect could not be explained by differences in pharmacokinetics because plasma concentrat ions of total and free rhIGF-I increased linearly in a dose-dependent manner. in summary, these findings demonstrate that peripherally admin istered rhIGF-I after bilateral sciatic nerve crush in mice resulted i n a dose-dependent, marked enhancement of regeneration as measured bio chemically and behaviorally.