Figure 1.
Chemical structure of UWA-101.
Figure 2.
ON-time and quality of ON-time.
A. UWA-101 (3, 6, 10 mg/kg), when co-administered with L-DOPA, significantly increased duration of ON-time compared to L-DOPA/ vehicle treatment. Following administration of L-DOPA/ vehicle, marmosets had a mean duration of ON-time of 221.8±19.0 min. Combining L-DOPA with UWA-101 3 or 6 mg/kg both led to an additional 62 min of ON-time, while UWA-101 10 mg/kg led to an additional 72.2 min of ON-time (all P<0.05). B. UWA-101 (1, 3, 6, 10 mg/kg), in combination with L-DOPA, did not alter duration of ON-time with dyskinesia. Following administration of L-DOPA/ vehicle, the mean duration of ON-time with dyskinesia was 190.0±26.9 min. This was not significantly modified when UWA-101 was added to L-DOPA (all P>0.05). C. UWA-101 (1, 3, 6, 10 mg/kg), in combination with L-DOPA, significantly increased duration of ON-time without dyskinesia. The administration of L-DOPA/ vehicle led to a mean duration of ON-time without dyskinesia of 30.0±15.8 min. When co-administered with L-DOPA, UWA-101 (1, 3, 6, 10 mg/kg) , increased duration of ON-time without dyskinesia by 64 min, 80 min, 64 min and 90 min, respectively (P<0.05 for UWA-101 1 and 6 mg/kg, and P<0.01 for UWA-101 3 and 10 mg/kg). D. UWA-101 (10 mg/kg) significantly extended duration of ON-time without disabling dyskinesia, when combined with L-DOPA. Following L-DOPA/ vehicle treatment, duration of ON-time without disabling dyskinesia was 152.0±32.1 min. The co-administration of UWA-101 10 mg/kg added 94 min (P<0.01). *: P<0.05; **: P<0.01. Data are expressed as the mean ± SEM.
Figure 3.
A. Dyskinesia time course. At no time during the 6 h observation period did UWA-101 (1, 3, 6, 10 mg/kg) exacerbate the severity of dyskinesia when compared to L-DOPA/ vehicle treatment (P>0.05). Each time point represents the cumulated dyskinesia scores for every 5 min observation period during the preceding 60 min. The maximal possible score (most severe disability) was 24. On the y-axis, mild = 6, moderate = 12, marked = 18, severe = 24. B. Peak dose dyskinesia. UWA-101 (1, 3, 6, 10 mg/kg) in combination with L-DOPA did not exacerbate the severity of peak dose dyskinesia (sum of dyskinesia score for every 5 min observation period from 80–140 min following treatment, during which dyskinesia severity was maximal) when compared to L-DOPA/ vehicle treatment (P>0.05). Median peak dose dyskinesia severity was moderate – marked in each treatment group. The maximal possible score (most severe disability) was 24. On the y-axis, mild = 6, moderate = 12, marked = 18, severe = 24. Data are expressed as the median (A) and as the median with individual scores (B). ns: not significant.
Figure 4.
A. UWA-101 (6, 10 mg/kg) exacerbated the severity of psychosis-like behaviours. The addition of UWA-101 6 mg/kg to L-DOPA resulted in significantly more severe psychosis-like behaviours when compared to L-DOPA/ vehicle (at time 120 min post drug administration, P<0.001). L-DOPA/ UWA-101 6 mg/kg also led to significantly more severe psychosis-like behaviours than the L-DOPA/ UWA-101 1 mg/kg (120 min and 180 min post drug administration, P<0.01 and P<0.05, respectively) and the L-DOPA/ UWA-101 3 mg/kg (60 min and 120 min post drug administration, P<0.05 and P<0.001, respectively) treatments. Psychosis-like behaviours were also significantly more severe when L-DOPA/ UWA-101 10 mg/kg was compared to L-DOPA/ vehicle (60 and 120 min post drug administration, both P<0.05), L-DOPA/ UWA-101 1 mg/kg (60 min post drug administration, P<0.01) and L-DOPA/ UWA-101 3 mg/kg (60 min and 120 min post drug administration, P<0.001 and P<0.01, respectively) treatments. Each time point represents the cumulated psychosis-like behaviours scores for every 5 min observation period during the preceding 60 min. The maximal possible score (most severe disability) was 24. On the y-axis, mild = 6, moderate = 12, marked = 18, severe = 24. The crosses on the graph represent time points for which there is statistical significance. B. UWA-101, in combination with L-DOPA, did not alter duration of ON-time with psychosis-like behaviours. Following administration of L-DOPA/ vehicle, the mean duration of ON-time with psychosis-like behaviours was 188.0±24.8 min. This was not significantly modified when UWA-101 (1, 3, 6, 10 mg/kg) was added to L-DOPA (all P>0.05). *: P<0.05 when compared to vehicle; ***: P<0.001 when compared to vehicle; #: P<0.05 when compared to UWA-101 1 mg/kg; ##: P<0.01 when compared to UWA-101 1 mg/kg; †: P<0.05 when compared to UWA-101 3 mg/kg; ††: P<0.01 when compared to UWA-101 3 mg/kg; †††: P<0.001 when compared to UWA-101 3 mg/kg. Data are expressed as the median (B) and as the mean ± SEM (B).
Table 1.
Order of treatments.