Abstract
Zonisamide is a relatively recent drug for Parkinson's disease. Multiple hypotheses have been proposed to explain the antiparkinsonian effects of zonisamide. However, it is still unclear whether the effect of zonisamide is mainly due to dopaminergic modification in the striatum, or if zonisamide works through nondopaminergic pathways. We conducted the present study to determine the mechanism that is mainly responsible for zonisamide's effects in Parkinson's disease. We examined the effects of zonisamide on motor symptoms in a hemiparkinsonian rat model when administered singly, coadministered with levodopa, a dopamine precursor, or apomorphine, a D1 and D2 dopamine receptor agonist. We used 6-hydroxydopamine-lesioned hemiparkinsonian rats, which were allocated to one of five groups: 14 rats received levodopa only (6 mg/kg), 12 rats received levodopa (6 mg/kg) plus zonisamide (50 mg/kg), six rats received apomorphine only (0.05 mg/kg), six rats received apomorphine (0.05 mg/kg) plus zonisamide (50 mg/kg), and six rats received zonisamide only (50 mg/kg). The drugs were administered once daily for 15 days. We evaluated abnormal involuntary movement every 20 min during a 3 h period following the injection of drugs on treatment Days 1, 8, and 15. Western blot analyses for dopamine decarboxylase and vesicular monoamine transferase-2 were performed using striatal tissues in the lesioned side of rats in the levodopa only group (n = 6) and levodopa plus zonisamide group (n = 4). Levodopa-induced abnormal involuntary movement was significantly enhanced by coadministration of zonisamide. In contrast, zonisamide had no effect on apomorphine-induced abnormal involuntary movement. Zonisamide monotherapy did not induce abnormal involuntary movement. Zonisamide did not affect striatal expression of dopamine decarboxylase or vesicular monoamine transferase-2. In conclusion, zonisamide appears to generate its antiparkinsonian effects by modulating levodopa-dopamine metabolism in the parkinsonian striatum.
Highlights
Parkinson’s disease (PD) is a neurodegenerative disease characterized by motor symptoms such as tremor, akinesia, hypokinesia, rigidity, and postural disturbance [1]. e most effective treatment for PD is dopamine replacement therapy using the dopamine precursor, L-3,4-dihydroxyphenylalanine [2]
Methaesulfonamide is an antiparkinsonian drug developed relatively recently. It has been primarily used as an antiepileptic drug and has been reported to be efficacious in the treatment of PD [4]. e beneficial effects of zonisamide in PD were serendipitously found in a patient who had epilepsy and PD [4]
We conducted the present study to determine the mechanism that is mainly responsible for zonisamide’s effects in PD. e aim of the present study is to examine the effects of zonisamide on motor symptoms in a hemiparkinsonian rat when administered singly, coadministered with levodopa, a dopamine precursor, or apomorphine, a D1 and D2 dopamine receptor agonist
Summary
Parkinson’s disease (PD) is a neurodegenerative disease characterized by motor symptoms such as tremor, akinesia, hypokinesia, rigidity, and postural disturbance [1]. e most effective treatment for PD is dopamine replacement therapy using the dopamine precursor, L-3,4-dihydroxyphenylalanine (levodopa, L-dopa) [2]. Is rat responds very sharply to dopaminergic stimulation in the lesioned striatum and presents marked abnormal involuntary movements (AIMs) in its body contralateral to the lesion [11, 12]. Behavioral analysis of this animal model may shed light on the mechanisms of zonisamide. E aim of the present study is to examine the effects of zonisamide on motor symptoms in a hemiparkinsonian rat when administered singly, coadministered with levodopa, a dopamine precursor, or apomorphine, a D1 and D2 dopamine receptor agonist We conducted the present study to determine the mechanism that is mainly responsible for zonisamide’s effects in PD. e aim of the present study is to examine the effects of zonisamide on motor symptoms in a hemiparkinsonian rat when administered singly, coadministered with levodopa, a dopamine precursor, or apomorphine, a D1 and D2 dopamine receptor agonist
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