Zonisamide-induced long-lasting recovery of dopaminergic neurons from MPTP-toxicity

Choudhury, Mohammed E.; Moritoyo, Takashi; Kubo, Madoka; Kyaw, Win Thiri; Yabe, Hayato; Nishikawa, Noriko; Nagai, Masahiro; Matsuda, Seiji; Nomoto, Masahiro

doi:10.1016/j.brainres.2011.02.017

Cited by 33 publications

(28 citation statements)

References 22 publications

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“…In vitro and in vivo evidence in 6-OHDA, MPTP and rotenone models; dose-dependent neuroprotection of DA neurons in 6-OHDA, MPTP and rotenone models in vivo and in vitro, albeit with conflicting doses 46,[205][206][207] Symptomatic improvement in motor function in an RCT 208…”

Section: Calcium Channel Blockadementioning

confidence: 99%

The ongoing pursuit of neuroprotective therapies in Parkinson disease

2014

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Many agents developed for neuroprotective treatment of Parkinson disease (PD) have shown great promise in the laboratory, but none have translated to positive results in patients with PD. Potential neuroprotective drugs, such as ubiquinone, creatine and PYM50028, have failed to show any clinical benefits in recent high-profile clinical trials. This 'failure to translate' is likely to be related primarily to our incomplete understanding of the pathogenic mechanisms underlying PD, and excessive reliance on data from toxin-based animal models to judge which agents should be selected for clinical trials. Restricted resources inevitably mean that difficult compromises must be made in terms of trial design, and reliable estimation of efficacy is further hampered by the absence of validated biomarkers of disease progression. Drug development in PD dementia has been mostly unsuccessful; however, emerging biochemical, genetic and pathological evidence suggests a link between tau and amyloid-β deposition and cognitive decline in PD, potentially opening up new possibilities for therapeutic intervention. This Review discusses the most important 'druggable' disease mechanisms in PD, as well as the most-promising drugs that are being evaluated for their potential efficiency in treatment of motor and cognitive impairments in PD.

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Section: Calcium Channel Blockadementioning

confidence: 99%

The ongoing pursuit of neuroprotective therapies in Parkinson disease

2014

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“…Zonisamide was approved in Japan [2009] as adjunctive therapy with levodopa in previously treated adult patients with PD. In animal models it appears to elevate TH levels and reduce neuroinflammation, and thereby mitigate the toxicity of MPTP [218, 219]. …”

Section: Introductionmentioning

confidence: 99%

A Synopsis on the Role of Tyrosine Hydroxylase in Parkinson’s Disease

Tabrez¹,

Jabir²,

Shakil³

et al. 2012

CNSNDDT

125

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Parkinson's disease (PD) is a common chronic progressive neurodegenerative disorder in elderly people. A consistent neurochemical abnormality in PD is degeneration of dopaminergic neurons in substantia nigra pars compacta, leading to a reduction of striatal dopamine (DA) levels. As tyrosine hydroxylase (TH) catalyses the formation of L-dihydroxyphenylalanine (L-DOPA), the rate-limiting step in the biosynthesis of DA, the disease can be considered as a TH-deficiency syndrome of the striatum. Problems related to PD usually build up when vesicular storage of DA is altered by the presence of either α-synuclein protofibrils or oxidative stress. Phosphorylation of three physiologically-regulated specific sites of N-terminal domain of TH is vital in regulating its kinetic and protein interaction. The concept of physiological significance of TH isoforms is another interesting aspect to be explored further for a comprehensive understanding of its role in PD. Thus, a logical and efficient strategy for PD treatment is based on correcting or bypassing the enzyme deficiency by the treatment with L-DOPA, DA agonists, inhibitors of DA metabolism or brain grafts with cells expressing a high level of TH. Neurotrophic factors are also attracting the attention of neuroscientists because they provide the essential neuroprotective and neurorestorative properties to the nigrostriatal DA system. PPAR-γ, a key regulator of immune responses, is likewise a promising target for the treatment of PD, which can be achieved by the use of agonists with the potential to impact the expression of pro- and anti-inflammatory cytokines at the transcriptional level in immune cells via expression of TH. Herein, we review the primary biochemical and pathological features of PD, and describe both classical and developing approaches aimed to ameliorate disease symptoms and its progression.

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“…In vitro and animal models have demonstrated that zonisamide has modulator effects on oxidative stress, intracellular Ca 2+ signaling, and caspase-3 activity [89], as well as neuroprotective effects in MPTP-induced dopaminergic neuronal degeneration [90]. Currently, the ZONIST trial is investigating the neuroprotection by zonisamide in early PD [91].…”

Section: Antioxidantsmentioning

confidence: 99%

Pathogenesis-Targeted, Disease-Modifying Therapies in Parkinson Disease

2014

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Parkinson disease is an inexorably progressive neurodegenerative disorder. Multiple attempts have been made to establish therapies for Parkinson disease which provide neuroprotection or disease modification-two related, but not identical, concepts. However, to date, none of these attempts have succeeded. Many challenges exist in this field of research, including a complex multisystem disorder that includes dopaminergic and non-dopaminergic features; poorly understood and clearly multifaceted disease pathogenic mechanisms; a lack of reliable animal models; an absence of effective biomarkers of disease state, progression, and target engagement; and the confounding effects of potent symptomatic therapy. In this article, we will review previous, ongoing, and potential future trials designed to alter the progressive course of the disease from the perspective of the targeted underlying pathogenic mechanisms.

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Zonisamide-induced long-lasting recovery of dopaminergic neurons from MPTP-toxicity

Cited by 33 publications

References 22 publications

The ongoing pursuit of neuroprotective therapies in Parkinson disease

The ongoing pursuit of neuroprotective therapies in Parkinson disease

A Synopsis on the Role of Tyrosine Hydroxylase in Parkinson’s Disease

Pathogenesis-Targeted, Disease-Modifying Therapies in Parkinson Disease

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