Figure 6.
MM218 increases survival in SOD1G93A mice. A, Kaplan–Meier curve for survival of SOD1G93A mice (B6.Cg) treated with vehicle (n = 13) or 10 μm MM218 (n = 12) in the minipump (estimated concentrations in CSF are in the low nanomolar range). SOD1G93A mice received continuous intracerebroventricular infusion through osmotic minipump for 56 d starting from 98 d of age (implantation, first arrow), with a pump replacement after 28 d of treatment (second arrow). Log–rank Mantel–Cox test was done comparing vehicle-treated animals. B, Survival length of SOD1G93A mice treated with vehicle and MM218, 1 μm (n = 11) and 10 μm. MM218 increased life expectation in SOD1G93A mice with a dose–response effect (p < 0.01, post test for linear trend). There was no difference in survival between vehicle-treated and nontreated SOD1G93A mice (n = 12). Data are shown as mean ± SEM. *p < 0.05 by one-way ANOVA, Tukey's multiple-comparisons test. C, SOD1G93A mice treated with MM218 at 10 μm showed a tendency toward better motor function, as assessed by the Rotarod test. Data were analyzed up to 137 d, when all animals in each group were still alive. Data (mean ± SEM) are expressed in seconds and were evaluated by two-way ANOVA for repeated measures: p = 0.4, for treatment factor; p < 0.01, for age factor; p = 0.52, for interaction. D, Paralysis, assessed as the age at which the mice were no longer able to do the Rotarod test. The mean age was significantly different in the MM218-treated (167 ± 2) and vehicle-treated (161 ± 3) mice; *p < 0.05 by Student's t test. E, Quantification of Nissl-stained motor neurons (MNs > 250 μm2) in lumbar spinal cord hemisections from SOD1G93A mice treated with vehicle and MM218, 10 μm, at end-stage disease. Data are shown as mean ± SEM (n = 5). *p < 0.05 by Student's t test. Representative Nissl-stained lumbar spinal cord hemisections from vehicle (Veh)- and MM218-treated animals are shown. Scale bar, 400 μm.