Zonisamide attenuates the severity of levodopa-induced dyskinesia via modulation of the striatal serotonergic system in a rat model of Parkinson's disease

Tohge, Rie; Kaneko, Satoshi; Morise, Satoshi; Oki, Mitsuaki; Takenouchi, Norihiro; Murakami, Aya; Nakamura, Masataka; Kusaka, Hirofumi; Yakushiji, Yusuke

doi:10.1016/j.neuropharm.2021.108771

Cited by 7 publications

(6 citation statements)

References 49 publications

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“…The AIMs of L-DOPA in the ZNS group were enhanced and prolonged, and the peaked AIMs score worsened slightly. On the other hand, recent reports have shown that ZNS ameliorates LID in PD model rats [18,19], which included L-DOPA (12 mg/kg) and ZNS (26 mg/kg) injections twice a day for two weeks and AIMs evaluation. The AIMs of the L-DOPA with ZNS-injected group were statistically lower than those of the L-DOPA-only injected group 140 min after injection [18].…”

Section: Discussionmentioning

confidence: 99%

“…Although the precise mechanism, by which ZNS affects LID is not fully elucidated, previous studies have demonstrated that L-DOPA with ZNS treatment upregulates expression of several key molecules in the striatum of 6-OHDA-treated mice, including prodynorphin, D1 and D2 receptors, brain-derived neurotrophic factor, serotonin transporter, and 5HT1A receptor [18,19]. Additionally, recording of neuronal activity in the SNr, one of output nuclei of the basal ganglia, in PD model mice treated with L-DOPA and ZNS injections has revealed changes in response to motor cortical stimulation [16].…”

Section: Discussionmentioning

confidence: 99%

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Behavioral effects of zonisamide on L-DOPA-induced dyskinesia in Parkinson’s disease model mice

Sano

Nambu

2023

Preprint

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Zonisamide (ZNS; 1,2-benzisoxazole-3-methanesulfonamide) was initially developed and is commonly used as an anticonvulsant drug. However, it has also shown beneficial effects on Parkinson's disease (PD), a progressive neurodegenerative disorder caused by the loss of dopaminergic neurons in the midbrain. Recent clinical studies have suggested that ZNS can also have beneficial effects on L-DOPA-induced dyskinesia (LID), which is a major side effects of long-term L-DOPA treatments for PD. In the present study, we examined the behavioral effects of ZNS on LID in PD model mice. Acute ZNS treatment did not have any observable behavioral effects on LID. Contrastingly, chronic ZNS treatment with L-DOPA delayed the peak of LID and reduced the severity of LID before the peak, but increased the duration of LID in a dose-dependent manner of ZNS, compared to PD model mice treated with L-DOPA alone. Thus, ZNS appears to have both beneficial and adverse effects on LID.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Behavioral effects of zonisamide on L-DOPA-induced dyskinesia in Parkinson’s disease model mice

Sano

Nambu

2023

Preprint

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“…The AIMs of l -DOPA in the ZNS group were enhanced and prolonged, and the peaked AIMs score worsened slightly. Recent reports have shown that ZNS ameliorates LID in PD model rats (Oki et al, 2017 ; Tohge et al, 2021 ), which included l -DOPA (12 mg/kg) and ZNS (26 mg/kg) injections twice a day for 2 weeks and AIMs evaluation. The AIMs of the l -DOPA with ZNS-injected group were statistically lower than those of the l -DOPA-only injected group 140 min after injection (Oki et al, 2017 ).…”

Section: Discussionmentioning

confidence: 99%

“…Although the precise mechanism, by which ZNS affects LID is not fully elucidated, previous studies have demonstrated that l -DOPA with ZNS treatment normalizes the expression of several key molecules in the striatum, such as adenosine A 2A , endocannabinoid CB 1 , and 5-HT 1B receptors, which are upregulated in 6-OHDA-treated rats with LID (Oki et al, 2017 ; Tohge et al, 2021 ). Additionally, the recording of neuronal activity in the SNr, one of the output nuclei of the basal ganglia, in PD model mice treated with l -DOPA and ZNS injections has revealed changes in response to motor cortical stimulation (Sano and Nambu, 2019 ).…”

Section: Discussionmentioning

confidence: 99%

Behavioral effects of zonisamide on L-DOPA-induced dyskinesia in Parkinson's disease model mice

Sano

Nambu

2023

Front. Aging Neurosci.

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Zonisamide (ZNS; 1,2-benzisoxazole-3-methanesulfonamide) was initially developed and is commonly used as an anticonvulsant drug. However, it has also shown its beneficial effects on Parkinson's disease (PD), a progressive neurodegenerative disorder caused by the loss of dopaminergic neurons in the midbrain. Recent clinical studies have suggested that ZNS can also have beneficial effects on L-DOPA-induced dyskinesia (LID), which is a major side effect of long-term L-DOPA treatments for PD. In the present study, we examined the behavioral effects of ZNS on LID in PD model mice. Acute ZNS treatment did not have any observable behavioral effects on LID. Contrastingly, chronic ZNS treatment with L-DOPA delayed the peak of LID and reduced the severity of LID before the peak but increased the duration of LID in a dose-dependent manner of ZNS compared to PD model mice treated with L-DOPA alone. Thus, ZNS appears to have both beneficial and adverse effects on LID.

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“…As these neurons lack a negative feedback mechanism for the regulation of synaptic DA levels, these processes are highly uncontrolled, leading to persistent and prolonged abnormal DA release that significantly increases the striatal DA level and ultimately leads to LID. 23 Several 5‐HT receptor agonists, such as NLX‐112, 24 zonisamide, 25 and buspirone, 26 have been used to ameliorate dyskinesia in recent preclinical and clinical trials. Eltoprazine, a 5‐HT1A/B autoreceptor agonist, inhibits DA release from 5‐HT neurons and has been shown to effectively ameliorate dyskinesia in rats 27 and patients 28 with LID.…”

Section: Introductionmentioning

confidence: 99%

Eltoprazine modulated gamma oscillations on ameliorating L‐dopa‐induced dyskinesia in rats

Wang

et al. 2023

CNS Neurosci Ther

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AimParkinson's disease (PD) is a pervasive neurodegenerative disease, and levodopa (L‐dopa) is its preferred treatment. The pathophysiological mechanism of levodopa‐induced dyskinesia (LID), the most common complication of long‐term L‐dopa administration, remains obscure. Accumulated evidence suggests that the dopaminergic as well as non‐dopaminergic systems contribute to LID development. As a 5‐hydroxytryptamine 1A/1B receptor agonist, eltoprazine ameliorates dyskinesia, although little is known about its electrophysiological mechanism. The aim of this study was to investigate the cumulative effects of chronic L‐dopa administration and the potential mechanism of eltoprazine's amelioration of dyskinesia at the electrophysiological level in rats.MethodsNeural electrophysiological analysis techniques were conducted on the acquired local field potential (LFP) data from primary motor cortex (M1) and dorsolateral striatum (DLS) during different pathological states to obtain the information of power spectrum density, theta‐gamma phase–amplitude coupling (PAC), and functional connectivity. Behavior tests and AIMs scoring were performed to verify PD model establishment and evaluate LID severity.ResultsWe detected exaggerated gamma activities in the dyskinetic state, with different features and impacts in distinct regions. Gamma oscillations in M1 were narrowband manner, whereas that in DLS had a broadband appearance. Striatal exaggerated theta‐gamma PAC in the LID state contributed to broadband gamma oscillation, and aperiodic‐corrected cortical beta power correlated robustly with aperiodic‐corrected gamma power in M1. M1–DLS coherence and phase‐locking values (PLVs) in the gamma band were enhanced following L‐dopa administration. Eltoprazine intervention reduced gamma oscillations, theta–gamma PAC in the DLS, and coherence and PLVs in the gamma band to alleviate dyskinesia.ConclusionExcessive cortical gamma oscillation is a compelling clinical indicator of dyskinesia. The detection of enhanced PAC and functional connectivity of gamma‐band oscillation can be used to guide and optimize deep brain stimulation parameters. Eltoprazine has potential clinical application for dyskinesia.

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Zonisamide attenuates the severity of levodopa-induced dyskinesia via modulation of the striatal serotonergic system in a rat model of Parkinson's disease

Cited by 7 publications

References 49 publications

Behavioral effects of zonisamide on L-DOPA-induced dyskinesia in Parkinson’s disease model mice

Behavioral effects of zonisamide on L-DOPA-induced dyskinesia in Parkinson’s disease model mice

Behavioral effects of zonisamide on L-DOPA-induced dyskinesia in Parkinson's disease model mice

Eltoprazine modulated gamma oscillations on ameliorating L‐dopa‐induced dyskinesia in rats

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