Targeting reactive oxygen species, reactive nitrogen species and inflammation in MPTP neurotoxicity and Parkinson’s disease

Yokoyama, Hironori; Kuroiwa, Hayato; Yano, Ryohei; Araki, Tsutomu

doi:10.1007/s10072-008-0986-2

Cited by 77 publications

(42 citation statements)

References 80 publications

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“…Thus, DMF treatment, in particular mostly at the dose of 30 mg/kg, inhibiting the nuclear translocation of NF-jB and promoting the transcription of IjB-a, points toward representing a functional system for regulation of neuroinflammation in response to oxidative stress in the brain. However, oxidative stress is intimately linked as well not only to inflammation but also to other components of the neurodegenerative process, such as nitrosative stress (68). Various isoforms of the nitric oxide (NO) producing enzyme nitric oxide synthase (NOS) are elevated in PD, indicating an important critical role for NO in disease of the pathophysiology mechanisms, considering that increased expression of glial and neuronal NOS isoforms in astrocytes and neurons contributes to the synthesis of peroxynitrite synthesis, which leads to the generation of NT (nitrotyrosine) (27).…”

Section: Discussionmentioning

confidence: 99%

The Neuroprotective Effect of Dimethyl Fumarate in an MPTP-Mouse Model of Parkinson's Disease: Involvement of Reactive Oxygen Species/Nuclear Factor-κB/Nuclear Transcription Factor Related to NF-E2

Campolo

Casili

Biundo

et al. 2017

Antioxidants & Redox Signaling

126

101

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Aim: Oxidative stress plays a key role in Parkinson disease (PD), and nuclear transcription factor related to NF-E2 (Nrf-2) is involved in neuroprotection against PD. The aim of the present study was to investigate a role for nuclear factor-jB (NF-jB)/Nrf-2 in the neurotherapeutic action of dimethyl fumarate (DMF) in a mouse model of PD and in vitro in SHSY-5Y cells. Results: Daily oral gavage of DMF (10, 30, and 100 mg/kg) significantly reduced neuronal cell degeneration of the dopaminergic tract and behavioral impairments induced by four injections of the dopaminergic neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. Moreover, treatment with DMF prevented dopamine depletion, increased tyrosine hydroxylase and dopamine transporter activities, and also reduced the number of a-synucleinpositive neurons. Furthermore, DMF treatment upregulated the Nrf-2 pathway, increased NeuN + /Nrf-2 + cell number in the striatum, induced activation of manganese superoxide dismutase and heme oxygenase-1, and regulated glutathione levels. Moreover, DMF reduced interleukin 1 levels, cyclooxygenase 2 activity, and nitrotyrosine neuronal nitrite oxide synthase expression. This treatment also modulated microglia activation, restored nerve growth factor levels, and preserved microtubule-associated protein 2 alterations. The protective effects of DMF treatment, via Nrf-2, were confirmed in in vitro studies, through inhibition of Nrf-2 by trigonelline.Innovation: These findings demonstrate that DMF, both in a mouse model of PD and in vitro, provides, via regulation of the NF-jB/Nrf-2 pathway, novel cytoprotective modalities that further augment the natural antioxidant response in neurodegenerative and inflammatory disease models. Conclusion: These results support the thesis that DMF may constitute a promising therapeutic target for the treatment of PD. Antioxid. Redox Signal. 27, 453-471.

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Section: Discussionmentioning

confidence: 99%

The Neuroprotective Effect of Dimethyl Fumarate in an MPTP-Mouse Model of Parkinson's Disease: Involvement of Reactive Oxygen Species/Nuclear Factor-κB/Nuclear Transcription Factor Related to NF-E2

Campolo

Casili

Biundo

et al. 2017

Antioxidants & Redox Signaling

126

101

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“…lular and extracelluar damage to local neurons (55). The SN also has a very high iron content (48), which may further exacerbate oxidative damage by reacting with byproducts of DA metabolism to generate highly reactive radicals (16).…”

Section: Discussionmentioning

confidence: 99%

Neurodegeneration in an animal model of Parkinson's disease is exacerbated by a high-fat diet

Morris

Bomhoff

Stanford

et al. 2010

American Journal of Physiology-Regulatory, Integrative and Comp

131

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(PD), the clinical literature remains equivocal. We, therefore, sought to address the relationship between insulin resistance and nigrostriatal dopamine (DA) in a preclinical animal model. High-fat feeding in rodents is an established model of insulin resistance, characterized by increased adiposity, systemic oxidative stress, and hyperglycemia. We subjected rats to a normal chow or high-fat diet for 5 wk before infusing 6-hydroxydopamine (6-OHDA) into the medial forebrain bundle. Our goal was to determine whether a high-fat diet and the resulting peripheral insulin resistance would exacerbate 6-OHDA-induced nigrostriatal DA depletion. Prior to 6-OHDA infusion, animals on the high-fat diet exhibited greater body weight, increased adiposity, and impaired glucose tolerance. Two weeks after 6-OHDA, locomotor activity was tested, and brain and muscle tissue was harvested. Locomotor activity did not differ between the groups nor did cholesterol levels or measures of muscle atrophy. High-fat-fed animals exhibited higher homeostatic model assessment of insulin resistance (HOMA-IR) values and attenuated insulin-stimulated glucose uptake in fast-twitch muscle, indicating decreased insulin sensitivity. Animals in the high-fat group also exhibited greater DA depletion in the substantia nigra and the striatum, which correlated with HOMA-IR and adiposity. Decreased phosphorylation of HSP27 and degradation of IB␣ in the substantia nigra indicate increased tissue oxidative stress. These findings support the hypothesis that a diet high in fat and the resulting insulin resistance may lower the threshold for developing PD, at least following DA-specific toxin exposure. dopamine; diabetes; substantia nigra; striatum; insulin resistance CLINICAL STUDIES SUGGEST A LINK between type 2 diabetes (T2D) and Parkinson's disease (PD) (30,46), and between fat intake or adiposity and PD (1, 31, 34). Moreover, it was reported over 40 years ago that greater than 50% of PD patients exhibit abnormal glucose tolerance (4, 10) or diabetes (36). Despite this information, very little is known regarding the relationship of these diseases and the impact of comorbidity on their pathogenesis. By 2025, T2D is estimated to impact 300 million individuals (47), with the elderly at greatest risk (54), the population also at greatest risk for neurodegenerative diseases like PD. For these reasons, understanding the potential for T2D, obesity, high dietary fat intake, and insulin resistance to contribute to PD is critical. Although the exact cause of PD is unknown, various environmental factors such as aging, diet, and environmental toxin exposure have been implicated in contributing to its development (29, 34, 51). The idea that "multiple hits" play a role in PD degeneration is supported by the fact that 80% of dopamine (DA)-producing neurons must be lost for symptoms to appear (50). While diabetes and PD do not invariably coincide, several studies suggest that obesity may potentiate neuronal dysfunction or even neurodegeneration (reviewed in Ref. 11). High-f...

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“…MPP ϩ interferes with the mitochondrial complex-1, generates reactive oxygen species (ROS) and selectively damages dopaminergic neurons (15). Dopamine itself is also a highly-reactive molecule and naturally metabolized to produce ROS including hydrogen peroxide (H 2 O 2 ) via the monoamine oxidase pathway (16).…”

Section: Parkinson Disease (Pd)mentioning

confidence: 99%

The Endoplasmic Reticulum Stress Sensor, ATF6α, Protects against Neurotoxin-induced Dopaminergic Neuronal Death

Egawa

Yamamoto

Inoue

et al. 2011

Journal of Biological Chemistry

129

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Oxidative stress and endoplasmic reticulum (ER) stress are thought to contribute to the pathogenesis of various neurodegenerative diseases including Parkinson disease (PD), however, the relationship between these stresses remains unclear. ATF6␣ is an ER-membrane-bound transcription factor that is activated by protein misfolding in the ER and functions as a critical regulator of ER quality control proteins in mammalian cells. The goal of this study was to explore the cause-effect relationship between oxidative stress and ER stress in the pathogenesis of neurotoxin-induced model of PD. 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), a dopaminergic neurotoxin known to produce oxidative stress, activated ATF6␣ and increased ER chaperones and ER-associated degradation (ERAD) component in dopaminergic neurons. Importantly, MPTP induced formation of ubiquitin-immunopositive inclusions and loss of dopaminergic neurons more prominently in mice deficient in ATF6␣ than in wild-type mice. Cultured cell experiments revealed that 1-methyl-4-phenylpyridinium (MPP ؉ )-induced oxidative stress not only promoted phosphorylation of p38 mitogen-activated protein kinase (p38MAPK) but also enhanced interaction between phosphorylated p38MAPK and ATF6␣, leading to increment in transcriptional activator activity of ATF6␣. Thus, our results revealed a link between oxidative stress and ER stress by showing the importance of ATF6␣ in the protection of the dopaminergic neurons from MPTP that occurs through oxidative stress-induced activation of ATF6␣ and p38MAPK-mediated enhancement of ATF6␣ transcriptional activity.

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Targeting reactive oxygen species, reactive nitrogen species and inflammation in MPTP neurotoxicity and Parkinson’s disease

Cited by 77 publications

References 80 publications

The Neuroprotective Effect of Dimethyl Fumarate in an MPTP-Mouse Model of Parkinson's Disease: Involvement of Reactive Oxygen Species/Nuclear Factor-κB/Nuclear Transcription Factor Related to NF-E2

The Neuroprotective Effect of Dimethyl Fumarate in an MPTP-Mouse Model of Parkinson's Disease: Involvement of Reactive Oxygen Species/Nuclear Factor-κB/Nuclear Transcription Factor Related to NF-E2

Neurodegeneration in an animal model of Parkinson's disease is exacerbated by a high-fat diet

The Endoplasmic Reticulum Stress Sensor, ATF6α, Protects against Neurotoxin-induced Dopaminergic Neuronal Death

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