Zonisamide Applications in Parkinson's Disease

Zonisamide, originally developed as an anticonvulsant, has been repurposed over the past two decades as an adjunctive therapy for Parkinson’s disease. Its multifaceted mechanisms—ranging from inhibition of monoamine oxidase-B and blockade of T-type calcium channels to modulation of dopamine turnover and mitochondrial function—contribute to improvements in motor symptoms, reduction of “off” time and potential neuroprotective effects. Clinical studies have demonstrated that, at doses of 25–50 mg per day, zonisamide reduces motor fluctuations without exacerbating dyskinesia and may ameliorate non-motor features such as sleep disturbances and mood disorders. Preclinical work further suggests benefits in mitochondrial β-oxidation and attenuation of microglial-driven neuroinflammation. Collectively, these findings underscore the global significance of zonisamide as a well-tolerated, orally administered agent that complements standard dopaminergic therapy, offering a pragmatic pathway to extend functional mobility and quality of life in people with Parkinson’s disease.

Research from Nature Portfolio

Recent longitudinal imaging work has examined neuroinflammatory trajectories in early Parkinson’s disease under dopamine‐replacement regimens with and without adjunctive zonisamide. Over a one-year period, positron emission tomography revealed progressive microglial activation across parieto-occipital regions in all patients. However, those receiving zonisamide exhibited significantly lower binding of a microglial tracer, suggesting an anti-inflammatory or neuroprotective effect. Concurrent measures of striatal dopamine transporter availability indicated relative preservation of binding in the nucleus accumbens in the zonisamide group. Clinically, participants treated with zonisamide showed improved attentional performance, hinting at functional benefits that parallel the imaging findings.

Zonisamide Applications in Parkinson's Disease publication trend

The graph below shows the total number of articles in zonisamide applications in parkinson's disease across all publications each year (not limited to Nature Index journals).

Technical terms

Dopaminergic neurons: Nerve cells that synthesise and release the neurotransmitter dopamine, loss of which underlies Parkinsonian motor deficits.

L-DOPA-induced dyskinesia: Involuntary, often choreiform movements arising from long-term levodopa therapy.

Neuroinflammation: Activation of glial cells and associated immune mediators within the central nervous system.

β-oxidation: Mitochondrial metabolic pathway that breaks down fatty acids to generate energy.

Monoamine oxidase-B (MAO-B): Enzyme that degrades dopamine and other monoamines, targeted to prolong synaptic dopamine availability.

Microglia: Resident immune cells of the brain that mediate inflammatory responses and can influence neurodegeneration.

References

1. Zonisamide for the Treatment of Parkinson Disease: A Current Update. Frontiers in Neuroscience (2020).
2. Zonisamide Administration Improves Fatty Acid β-Oxidation in Parkinson’s Disease. Cells (2018).
3. Zonisamide Ameliorates Microglial Mitochondriopathy in Parkinson’s Disease Models. Brain Sciences (2022).
4. Zonisamide improves wearing off in Parkinson's disease without exacerbating dyskinesia: Post hoc analysis of phase 2 and phase 3 clinical trials. Journal of the Neurological Sciences (2021).
5. Zonisamide effects on sleep problems and depressive symptoms in Parkinson’s disease. Brain and Behavior (2021).
6. Neuroinflammation following anti-parkinsonian drugs in early Parkinson’s disease: a longitudinal PET study. Scientific Reports (2024).
7. Behavioral effects of zonisamide on L-DOPA-induced dyskinesia in Parkinson's disease model mice. Frontiers in Aging Neuroscience (2023).
8. Role of zonisamide in advanced Parkinson’s disease: a randomized placebo-controlled study. Neurological Sciences (2024).