Table 1.
Pharmacokinetic properties of PF-01247324 dosed in C57BL6 mice (n = 3 per dose level).
Fig 1.
Oral administration of PF-01247324 partially reverses motor incoordination in transgenic mice overexpressing Nav1.8 in cerebellar Purkinje neurons.
A. Latency to fall from an inverted wire grid was measured in L7–1.8TG mice administered either PF-01247324 or vehicle, and in their wildtype littermates. Behavioral testing was performed one hour after dosing. Differences between the three groups were significant (one-way ANOVA, p = 0.0014). L7–1.8TG mice in the vehicle group performed significantly worse than WT mice. L7–1.8TG mice that received oral dosing of PF-01247324 had significantly improved performance in this assay. B. In the rotarod test, significant differences in motor coordination were observed (one-way ANOVA, p = 0.0006). L7–1.8TG mice in the vehicle group were able to stay on the rotating beam for less time than WT mice, indicating a deficit in motor coordination. Oral administration of PF-01247324 to L7–1.8TG mice significantly improved their performance compared to vehicle-treated mice of the same genotype. C. Grip strength was similar in each of the three groups. One-way ANOVA, p = 0.7560. *, p<0.05 compared to WT vehicle group; #, p<0.05 compared to L7–1.8TG vehicle group, Dunnett’s post-hoc test. WT+vehicle, n = 8; L7–1.8TG+vehicle, n = 7; L7–1.8TG+PF-01247324, n = 6.
Fig 2.
Oral administration of PF-01247324 slightly improves MS-like deficits in the EAE model.
EAE symptom progression was scored on a 0 to 6 scale [9], with 0.5-point gradations for intermediate scores, as follows: 0, normal; 1, flaccid tail; 2, impaired righting reflex or wobbly gait but no clear weakness; 3, weakness of both hindlimbs or paralysis of a single hindlimb; 4, complete hindlimb paralysis; 5, primarily recumbent and unable to ambulate; 6, death. A. C57Bl/6 mice with EAE that were administered vehicle had stable symptom scores over the 6 h observation period. (All timepoints p>0.05 compared to baseline (BL), paired t-tests. n = 19.) B. C57Bl/6 mice with EAE that were administered PF-01247324 showed a slight improvement in symptom scores after dosing, when analyzed with paired t-tests to compare individual timepoints to pre-drug BL. (1 h, p = 0.3299; 2 h, p = 0.5426; 3 h, p = 0.0493; 4 h, p = 0.0084; 5 h, p = 0.0555; 6 h, p = 0.6649; paired t-tests compared to BL. n = 20.) However, a two-way ANOVA did not show significant improvement compared to vehicle control. *, p<0.05 compared to BL, paired t-test.