Zonisamide Increases Dopamine Turnover in the Striatum of Mice and Common Marmosets Treated With MPTP

Abstract

Abstract. The effect of zonisamide, an antiepileptic agent with anti-parkinsonian effects, was studied on dopamine neurons of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated C57 mice and common marmosets. Groups of mice (n = 8 -9) were treated with: MPTP (15 mg/ kg every 2 h ×4); MPTP plus zonisamide (40 mg/kg administered 1 h before each MPTP dose); MPTP plus selegiline (2 mg/kg administered 1 h before the first MPTP dose); zonisamide (40 mg/ kg ×4); and saline controls. Groups of common marmosets (n = 4 -6) were treated with: MPTP (2.5 mg/kg every 24 h ×3); MPTP plus zonisamide (40 mg/kg administered 1 h before each MPTP dose); MPTP plus selegiline (2 mg/ kg administered 1 h before the first MPTP dose); and saline controls. Brain dopamine and its metabolites were determined by HPLC. Dopamine content decreased in the striatum of MPTP-treated mice and monkeys. Co-administration of selegiline inhibited the effect of MPTP and dopamine contents were similar to those of the controls. Co-administration of zonisamide did not inhibit the effect of MPTP on dopamine content, but increased striatal dopamine turnover of animals treated with MPTP plus zonisamide more than in those treated with MPTP alone. MPTP treatment caused a compensatory increase of dopamine turnover in the striatum by remaining neurons. Zonisamide may help dopaminergic neurons by increasing striatal dopamine turnover following MPTP treatment.

Zonisamide Attenuates MPTP Neurotoxicity in Marmosets

“…2B, 4D), which is also in agreement with a previous study (22). In our previous study, we treated the animals with the same doses of MPTP and the dopamine contents decreased to 0.18 μg/mg, which is 1.1% that of the normal controls, and all of the MPTPtreated animals showed complete akinesia (13). Pretreatment with selegiline attenuated the reduction in the number of TH-positive neurons induced by MPTP toxicity ( Fig.…”

“…The MPTP neurotoxicity observed in this study was in good agreement with previous studies (17,18). The acute effects of MPTP end within 2 weeks following administration of MPTP (13,14), which set the time of taking samples from MPTP-treated marmosets for immunohistochemical study. Zonisamide was administered subcutaneously at a dose of 40 mg/kg in our study.…”

“…The irreversible and marked inhibitory effects of selegiline on MAO-B activity is well documented in previous studies (23,24), whereas zonisamide showed reversible, marginal inhibitory effects on MAO-B activity (9,11) and it increased the amount of TH in the striatum of MPTP-treated mice (12). Furthermore, in a previous biochemical study we demonstrated that zonisamide increased dopamine turnover in striatum treated with MPTP and also reduced akinesia score of MPTP-treated marmosets (13).…”

“…Zonisamide was administered subcutaneously at a dose of 40 mg/kg in our study. With this dose, the blood zonisamide concentration was 21.3 ± 1.2 μg/ml (mean ± S.D., n = 5) at 1 h after administration in common marmosets (13). This is well correlated with both the recommended blood concentration of zonisamide (10 -30 mg/ml) in patients with epilepsy (19) and to a previous report showing the maximum plasma concentration of zonisamide in rhesus monkeys (20).The major result of the present study was to demonstrate the effects of zonisamide on MPTP-induced reduction of TH-positive cells in the substantia nigra ( Fig.…”

“…Zonisamide attenuates 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced toxicity in mice by inhibition of MAO-B (11) and also by increasing the amount of tyrosine hydroxylase (TH) in the striatum (12). Zonisamide also increases dopamine turnover (DOPAC+HVA/DA) (13). Dopamine turnover is the compensatory mechanism of MPTP-treated dopaminergic neurons (14,15).…”