Figure 9.

NAC facilitates moderate improvement of the Npc1−/− mouse phenotypes of weight loss, tremor and shortened lifespan. (A) NAC-treated Npc1−/− groups (green, teal, red, and purple) reached their peak weight at a slightly later age than untreated Npc1−/− (orange), but this difference was not statistically significant (Kruskal–Wallis test, P = 0.2259). Following the peak of weight gain, NAC-treated Npc1−/− groups showed a rapid weight loss at a rate similar to or greater than that of untreated Npc1−/− mice. (B) Analysis of the tremor amplitude at 11 Hz in Npc1−/− mice indicated that at most timepoints (from 5–10 weeks) the tremor amplitude was lower in NAC-treated Npc1−/− groups relative to untreated Npc1−/− (line elevations by linear regression, P < 0.0001), but the rate of tremor acquisition did not differ among NAC-treated Npc1−/− and Npc1−/− groups (slopes by linear regression, P = 0.18). Means ± SD are shown. (C) NAC treatment significantly increased the lifespan of NAC-treated Npc1−/− mice relative to that of Npc1−/− at both the 125 mg/kg and 250 mg/kg dosages when initiated at 4 weeks (P = 0.0065 and 0.0003, respectively, log-rank test with Bonferroni's correction). Initiation of NAC treatment at the later timepoint of 6 weeks provided a modest increase of lifespan at the 125 mg/kg dosage, but no increase at the 250 mg/kg dosage relative to that of Npc1−/− (P = 0.03 and 0.1, respectively). The six experimental groups (n = 8 per group) were: untreated Npc1+/+, untreated Npc1−/−, Npc1−/− treated with 125 mg/kg NAC beginning at 4 weeks (P28), Npc1−/− treated with 250 mg/kg NAC beginning at 4 weeks, Npc1−/− treated with 125 mg/kg beginning at 6 weeks (P42), and Npc1−/− treated with 250 mg/kg NAC beginning at 6 weeks.