Zonisamide ameliorates levodopa-induced dyskinesia and reduces expression of striatal genes in Parkinson model rats

Oki, Mitsuaki; Kaneko, Satoshi; Morise, Satoshi; Takenouchi, Norihiro; Hashizume, Takanori; Tsuge, Ayako; Nakamura, Masataka; Wate, Reika; Kusaka, Hirofumi

doi:10.1016/j.neures.2017.04.003

Cited by 20 publications

(18 citation statements)

References 17 publications

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“…Our result is in agreement with a previous report that zonisamide enhances levodopa-induced rotational behavior in 6-OHDA-lesioned parkinsonian rats [20]. However, Oki et al have recently reported that zonisamide decreases levodopa-induced dyskinesia-like behavior in the same rat model of PD, although the effect was minimal [21]. In their experiment, the levodopa dose was 12 mg/kg twice a day, which is four times the dose per day that was used in our experiment.…”

Section: Discussionsupporting

confidence: 93%

Zonisamide Enhances Motor Effects of Levodopa, Not of Apomorphine, in a Rat Model of Parkinson’s Disease

Nishijima

Miki

Ueno

et al. 2018

Parkinson's Disease

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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.

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Section: Discussionsupporting

confidence: 93%

Zonisamide Enhances Motor Effects of Levodopa, Not of Apomorphine, in a Rat Model of Parkinson’s Disease

Nishijima

Miki

Ueno

et al. 2018

Parkinson's Disease

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“…Treatment of PD patients displaying no psychiatric comorbidities with cannabidiol, a naturally occurring cannabinoid constituent of cannabis which appears to lack psychoactive effects, improves quality of life measures, but does not improve Unified Parkinson’s Disease Rating Scale scores [195]. The toxin 6-OHDA has been found to increase CB1R mRNA expression [196], downregulate CB1R protein density in multiple brain regions [197,198] or not produce any changes [199]. These differential effects may be explained by the fact that 6-OHDA seems to change the expression of CB1R protein in a region- and time-specific manner [200].…”

Section: Glycerolipidsmentioning

confidence: 99%

The Role of Lipids in Parkinson’s Disease

Xicoy

Wieringa

Martens

2019

Cells

189

161

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Parkinson’s disease (PD) is a neurodegenerative disease characterized by a progressive loss of dopaminergic neurons from the nigrostriatal pathway, formation of Lewy bodies, and microgliosis. During the past decades multiple cellular pathways have been associated with PD pathology (i.e., oxidative stress, endosomal-lysosomal dysfunction, endoplasmic reticulum stress, and immune response), yet disease-modifying treatments are not available. We have recently used genetic data from familial and sporadic cases in an unbiased approach to build a molecular landscape for PD, revealing lipids as central players in this disease. Here we extensively review the current knowledge concerning the involvement of various subclasses of fatty acyls, glycerolipids, glycerophospholipids, sphingolipids, sterols, and lipoproteins in PD pathogenesis. Our review corroborates a central role for most lipid classes, but the available information is fragmented, not always reproducible, and sometimes differs by sex, age or PD etiology of the patients. This hinders drawing firm conclusions about causal or associative effects of dietary lipids or defects in specific steps of lipid metabolism in PD. Future technological advances in lipidomics and additional systematic studies on lipid species from PD patient material may improve this situation and lead to a better appreciation of the significance of lipids for this devastating disease.

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“…Zonisamide efficacy in treating LID has been investigated in preclinical studies carried out in 6-OHDA rat and mouse models of PD, showing improving and detrimental effects on LID, respectively. 132,133 A randomized, Phase IV, 12-week open-label pilot study investigating zonisamide tolerability and efficacy in treating LID has currently passed its completion date and has not been recently updated (ClinicalTrials.gov Identifier: NCT03034538).…”

Section: Other Targetsmentioning

confidence: 99%

Pathophysiological Mechanisms and Experimental Pharmacotherapy for L-Dopa-Induced Dyskinesia

Fabbrini¹,

Guerra²

2021

JEP

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L-dopa-induced dyskinesia (LID) is the most frequent motor complication associated with chronic L-dopa treatment in Parkinson’s disease (PD). Recent advances in the understanding of the pathophysiological mechanisms underlying LID suggest that abnormalities in multiple neurotransmitter systems, in addition to dopaminergic nigrostriatal denervation and altered dopamine release and reuptake dynamics at the synaptic level, are involved in LID development. Increased knowledge of neurobiological LID substrates has led to the development of several drug candidates to alleviate this motor complication. However, with the exception of amantadine, none of the pharmacological therapies tested in humans have demonstrated clinically relevant beneficial effects. Therefore, LID management is still one of the most challenging problems in the treatment of PD patients. In this review, we first describe the known pathophysiological mechanisms of LID. We then provide an updated report of experimental pharmacotherapies tested in clinical trials of PD patients and drugs currently under study to alleviate LID. Finally, we discuss available pharmacological LID treatment approaches and offer our opinion of possible issues to be clarified and future therapeutic strategies.

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Zonisamide ameliorates levodopa-induced dyskinesia and reduces expression of striatal genes in Parkinson model rats

Cited by 20 publications

References 17 publications

Zonisamide Enhances Motor Effects of Levodopa, Not of Apomorphine, in a Rat Model of Parkinson’s Disease

Zonisamide Enhances Motor Effects of Levodopa, Not of Apomorphine, in a Rat Model of Parkinson’s Disease

The Role of Lipids in Parkinson’s Disease

Pathophysiological Mechanisms and Experimental Pharmacotherapy for L-Dopa-Induced Dyskinesia

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