Zonisamide for the Treatment of Parkinson Disease: A Current Update

Abstract

Zonisamide has been used as an add-on treatment in order to overcome the deficiencies of the general therapies currently used to resolve the motor complications and non-motor symptoms of Parkinson disease. Various trials have been designed to investigate the mechanism of action and treatment effects of zonisamide in this condition. Most clinical trials of zonisamide in Parkinson disease were from Japan. The vast majority of studies used changes in the Unified Parkinson’s Disease Rating Scale (UPDRS) scores and daily “OFF” time as primary endpoints. Based on adequate randomized controlled trials, zonisamide is considered a safe and efficacious add-on treatment in Parkinson disease. The most convincing proof is available for a dosage of 25–50 mg, which was shown to lead to a significant reduction in the UPDRS III score and daily “OFF” time, without increasing disabling dyskinesia. Furthermore, zonisamide may play a beneficial role in improving non-motor symptoms in PD, including impulsive–compulsive disorder, rapid eye movement sleep behavior disorder, and dementia. Among the various mechanisms reported, inhibition of monoamine oxidase-B, blocking of T-type calcium channels, modulation of the levodopa–dopamine metabolism, modulation of receptor expression, and neuroprotection are the most often cited. The mechanisms underlying neuroprotection, including modulation of dopamine turnover, induction of neurotrophic factor expression, inhibition of oxidative stress and apoptosis, inhibition of neuroinflammation, modulation of synaptic transmission, and modulation of gene expression, have been most extensively studied. This review focuses on structure, pharmacokinetics, mechanisms, therapeutic effectiveness, and safety and tolerability of zonisamide in patients with Parkinson disease.

The Pharmacology and Clinical Efficacy of Antiseizure Medications: From Bromide Salts to Cenobamate and Beyond

“…Pregabalin was approved for generalized anxiety disorder in the European Union in 2006 [ 121 ]. Furthermore, based on randomized controlled trials, zonisamide is considered a safe and efficacious add-on treatment in Parkinson‘s disease [ 123 ], whereas no robust efficacy was reported for topiramate or levetiracetam [ 124 ]. Preliminary clinical data indicated that cannabidiol improved quality of life but not motor symptoms in patients with Parkinson’s disease [ 125 ], and larger randomized controlled trials are ongoing [ 124 ].…”

Kynurenic acid in neurodegenerative disorders—unique neuroprotection or double‐edged sword?

“…However, a number of compounds able to increase KYNA levels, through mechanisms distinct from interference with KP, successfully ameliorated L‐DOPA–induced dyskinesias. One of the interesting therapeutic options for PD seems to be the antiepileptic drug zonisamide, shown to reduce motor symptoms in patients with L‐DOPA–induced dyskinesias 215 . Zonisamide, apart from his broad pharmacological effects including inhibition of voltage‐gated sodium channels, T‐type calcium channels, and monoamine‐oxidase, has been shown to increase KYNA production 216 .…”

Zonisamide Ameliorates Microglial Mitochondriopathy in Parkinson’s Disease Models

“…The antiparkinsonian effects of ZNS have been reported in our previous studies on MPTP and in a 6-OHDA-treated animal model of PD, where we found that ZNS acts as a neuroprotectant against MPTP-induced dopaminergic neuronal degeneration by acting directly on neurones and astrocytes [ 14 , 15 , 16 , 17 ]. In addition to our studies, several research studies published by different groups have highlighted the antiparkinsonian effects of ZNS [ 33 ]. A study showed that ZNS reduced neuroinflammation by inhibiting Nav1.6 and TNFα in microglial cells in an MPTP-treated mouse model of PD.…”