Fig. 4

Dose response effects of PBT434 on neuron number and TH - positive varicosities. The effects on SNpc neuron number and motor function in response to escalating dose of PBT434 were assessed. 12–14 week old male C57BL/6 mice were lesioned using MPTP (60 mg/kg) resulting in an average SNpc lesion size of 55%. Treatment with PBT434 at 1,3,10, 30 or 80 mg/kg/day commenced 24 h after induction of lesion. a Mean number of SNpc neurons compared with the vehicle treated group (VEH)(±SEM). The proportion of SNpc cells rescued increased with increasing dose of PBT434. 3 mg (P < 0.05), 10 mg (P < 0.01), 30 mg (P < 0.001) and 80 mg/kg/day (P < 0.001) doses prevented a significant proportion of cell loss by day 21 (73 animals were studied from two separate MPTP experiments; One-way ANOVA paired with Games-Howell post hoc test). The red dotted line indicates the normal value. b Pole test was undertaken at day 20 post intoxication to test motor performance. As the dose of PBT434 increased there was a trend to improved turning behavior compared with the vehicle group while doses 30 mg/kg/day (P < 0.05) and 80 mg/kg/day (P < 0.01) showed a significant 2.5–3 fold improvement in the time to turn. (One-way ANOVA paired with Games-Howell post hoc test). The dashed line represents the average time taken by unlesioned animals to perform the task. c The abundance of tyrosine hydroxylase-positive varicosities in the caudate putamen was assessed by stereology at day 21 following MPTP (N = 6–7 animals per treatment). Following MPTP intoxication, TH -positive varicosities were reduced compared with unlesioned mice (* p < 0.05. One-way ANOVA, Tukey’s Post hoc comparison). Treatment with 30 or 80 mg/kg of PBT434 significantly increased varicosity abundance compared with untreated mice. d Light micrographs of the dorso-lateral tier of the caudate putamen showing individual tyrosine hydroxylase -positive varicosities (arrows), for unlesioned animals (UL), MPTP lesioned vehicle treated (VEH) or following PBT434 treatment (scale bar = 25 μm). e Western blots of the dorsal tier of the caudate putamen showed that treatment with PBT434 prevented the decline in levels of the presynaptic marker synaptophysin (SYNP), * p < 0.05, One-way ANOVA, Tukey Post hoc comparison). TP = total protein, OD = optical density