Zonisamide Treatment Delays Motor Neuron Degeneration and Astrocyte Proliferation in Wobbler Mice

Hirayama,

doi:10.4021/jnr59w

Cited by 4 publications

(7 citation statements)

References 23 publications

(32 reference statements)

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“…In addition, zonisamide has other pharmacological effects, such as protective effects for dopaminergic neurons [ 38 ], neuroprotection against cerebral ischemia [ 39 ], an anti-oxidant effect in epilepsy [ 40 ], and a radical scavenging action [ 41 , 42 ]. Furthermore, zonisamide attenuated degeneration of motor neurons and loss of astrocytes in a model mouse of amyotrophic lateral sclerosis [ 43 ], although the underlying mechanisms remain unsolved. The effect of zonisamide on sparing motor axons, however, has not been examined to date.…”

Section: Discussionmentioning

confidence: 99%

Zonisamide Enhances Neurite Elongation of Primary Motor Neurons and Facilitates Peripheral Nerve Regeneration In Vitro and in a Mouse Model

et al. 2015

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No clinically applicable drug is currently available to enhance neurite elongation after nerve injury. To identify a clinically applicable drug, we screened pre-approved drugs for neurite elongation in the motor neuron-like NSC34 cells. We found that zonisamide, an anti-epileptic and anti-Parkinson’s disease drug, promoted neurite elongation in cultured primary motor neurons and NSC34 cells in a concentration-dependent manner. The neurite-scratch assay revealed that zonisamide enhanced neurite regeneration. Zonisamide was also protective against oxidative stress-induced cell death of primary motor neurons. Zonisamide induced mRNA expression of nerve growth factors (BDNF, NGF, and neurotrophin-4/5), and their receptors (tropomyosin receptor kinase A and B). In a mouse model of sciatic nerve autograft, intragastric administration of zonisamide for 1 week increased the size of axons distal to the transected site 3.9-fold. Zonisamide also improved the sciatic function index, a marker for motor function of hindlimbs after sciatic nerve autograft, from 6 weeks after surgery. At 8 weeks after surgery, zonisamide was protective against denervation-induced muscle degeneration in tibialis anterior, and increased gene expression of Chrne, Colq, and Rapsn, which are specifically expressed at the neuromuscular junction. We propose that zonisamide is a potential therapeutic agent for peripheral nerve injuries as well as for neuropathies due to other etiologies.

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Section: Discussionmentioning

confidence: 99%

Zonisamide Enhances Neurite Elongation of Primary Motor Neurons and Facilitates Peripheral Nerve Regeneration In Vitro and in a Mouse Model

et al. 2015

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“…Besides animal PD models, the therapeutic potential of ZNS has been reported in various models of neurological diseases or neuronal injury [31][32][33][34]. ZNS protected spinal motor neurons in wobbler mouse motor neuron disease [32] and mouse embryo primary culture [33]. It induced messenger RNA expression of brain-derived neurotrophic factor, nerve growth factor, neurotrophin-4/5, and tropomyosin receptor kinase A and B [33].…”

Section: Discussionmentioning

confidence: 99%

Zonisamide cotreatment delays striatal dopamine transporter reduction in Parkinson disease: A retrospective, observational cohort study

Ikeda

Yanagihashi

Muramatsu

et al. 2018

Journal of the Neurological Sciences

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This study examined whether zonisamide (ZNS) cotreatment delays dopamine transporter (DAT) reduction on SPECT in Parkinson disease (PD) patients. The study participants met the following criteria: (i) age ≥ 40 years; (ii) HY stage = 2 or 3; (iii) average specific binding ratio (SBR) ≥2.00; (iv) levodopa administration without a prior history of ZNS use before the first DAT-SPECT (baseline). Attending physicians initially determined whether ZNS (25 mg/day) should be used or not. Levodopa and other anti-PD medications were not restricted. The second DAT-SPECT (endpoint) was conducted 1.2 ± 0.2 years after the first DAT-SPECT. Clinicoradiological changes of HY stage, UPDRS parts II to IV, dyskinesia subscore, and SBR were calculated. Statistical differences were analyzed by Student's t-test, ANOVA, or multilogistic analysis. ZNS cotreatment improved wearing off and prevented the development of dyskinesia without additional administration of selegiline, entacapone, and dopamine receptor agonists. The endpoint SBR reduced significantly in the non-ZNS group compared to the baseline (P < .01). The SBR decline rate reduced significantly in the ZNS group (P < .01). ZNS was an independent preventive factor for SBR reduction. These results suggested a beneficial potential that ZNS preserves striatal presynaptic DAT expression and slows disease progression in early-stage PD.

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“…With respect to inhibition of astrocytosis in edaravone-treated wobbler mice, the biological mechanism remains unclear in the present study. Astrocyte proliferation occurs together with loss of motor neurons in wobbler mice [ 17 ]. Therefore, edaravone treatment might decrease astrocyte proliferation as the result from attenuating motor neuron degeneration.…”

Section: Discussionmentioning

confidence: 99%

“…GFAP-immunoreactive astrocytes were investigated with a light microscope at magnification X 200. The number of astrocytes (cells/mm 2 ) was measured in the ventral horn of the C5-6 cord, using a computer-associated image analyzer software (MacScope ® ) as previously described [ 17 ].…”

Section: Methodsmentioning

confidence: 99%

Edaravone, a Free Radical Scavenger, Delayed Symptomatic and Pathological Progression of Motor Neuron Disease in the Wobbler Mouse

Ikeda

Iwasaki

2015

PLoS ONE

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Edaravone, a free radical scavenger is used widely in Japanese patients with acute cerebral infarction. This antioxidant could have therapeutic potentials for other neurological diseases. Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease that affects the upper and the lower motor neuron, leading to death within 3–5 years after onset. A phase III clinical trial of edaravone suggested no significant effects in ALS patients. However, recent 2nd double-blind trial has demonstrated therapeutic benefits of edaravone in definite patients diagnosed by revised El Escorial diagnostic criteria of ALS. Two previous studies showed that edaravone attenuated motor symptoms or motor neuron degeneration in mutant superoxide dismutase 1-transgenic mice or rats, animal models of familial ALS. Herein we examined whether this radical scavenger can retard progression of motor dysfunction and neuropathological changes in wobbler mice, sporadic ALS-like model. After diagnosis of the disease onset at the postnatal age of 3–4 weeks, wobbler mice received edaravone (1 or 10 mg/kg, n = 10/group) or vehicle (n = 10), daily for 4 weeks by intraperitoneal administration. Motor symptoms and neuropathological changes were compared among three groups. Higher dose (10 mg/kg) of edaravone treatment significantly attenuated muscle weakness and contracture in the forelimbs, and suppressed denervation atrophy in the biceps muscle and degeneration in the cervical motor neurons compared to vehicle. Previous and the present studies indicated neuroprotective effects of edaravone in three rodent ALS-like models. This drug seems to be worth performing the clinical trial in ALS patients in the United States of American and Europe, in addition to Japan.

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Zonisamide Treatment Delays Motor Neuron Degeneration and Astrocyte Proliferation in Wobbler Mice

Abstract: Background: Zonisamide (ZNS) had multifunctional effects on several kinds of neurons. Little is known about neuroprotective effects of ZNS on motor neurons. We aimed to study whether this drug can attenuate motor neuron degeneration in wobbler mice.

Cited by 4 publications

References 23 publications

Zonisamide Enhances Neurite Elongation of Primary Motor Neurons and Facilitates Peripheral Nerve Regeneration In Vitro and in a Mouse Model

Zonisamide Enhances Neurite Elongation of Primary Motor Neurons and Facilitates Peripheral Nerve Regeneration In Vitro and in a Mouse Model

Zonisamide cotreatment delays striatal dopamine transporter reduction in Parkinson disease: A retrospective, observational cohort study

Edaravone, a Free Radical Scavenger, Delayed Symptomatic and Pathological Progression of Motor Neuron Disease in the Wobbler Mouse

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