Evaluation of the effects of vitamin A supplementation on adult rat substantia nigra and striatum redox and bioenergetic states: Mitochondrial impairment, increased 3-nitrotyrosine and α-synuclein, but decreased D2 receptor contents

Oliveira, Marcos Roberto de; Oliveira, Max William Soares; Behr, Guilherme Antônio; Hoff, Mariana Leivas Müller; Rocha, Ricardo Fagundes da; Moreira, José Cláudio Fonseca

doi:10.1016/j.pnpbp.2008.12.020

Cited by 22 publications

(19 citation statements)

References 52 publications

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“…It has previously been shown that TH-positive nerve terminals within the striatum are reduced in transgenic mice overexpressing α-synuclein [13], and D 2 R is downregulated in some neurodegenerative diseases [60]. Recently, de Oliveira et al reported that D 2 R down-regulation occurred together with the upregulation of 3-nitrotyrosine and α-synuclein in a rodent oxidative stress model [61], although no cause-effect relationship was ascertained. In this study, we demonstrated that N-SYN not only led to the death of DA neurons in the SNpc, but also to a down-regulation of D 2 R in the striatum.…”

Section: Discussionmentioning

confidence: 99%

Nitrated α-Synuclein Induces the Loss of Dopaminergic Neurons in the Substantia Nigra of Rats

Xiang

et al. 2010

PLoS ONE

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BackgroundThe pathology of Parkinson's disease (PD) is characterized by the degeneration of the nigrostriatal dopaminergic pathway, as well as the formation of intraneuronal inclusions known as Lewy bodies and Lewy neurites in the substantia nigra. Accumulations of nitrated α-synuclein are demonstrated in the signature inclusions of Parkinson's disease. However, whether the nitration of α-synuclein is relevant to the pathogenesis of PD is unknown.Methodology/Principal FindingsIn this study, effect of nitrated α-synuclein to dopaminergic (DA) neurons was determined by delivering nitrated recombinant TAT-α-synuclein intracellular. We provide evidence to show that the nitrated α-synuclein was toxic to cultured dopaminergic SHSY-5Y neurons and primary mesencephalic DA neurons to a much greater degree than unnitrated α-synuclein. Moreover, we show that administration of nitrated α-synuclein to the substantia nigra pars compacta of rats caused severe reductions in the number of DA neurons therein, and led to the down-regulation of D2R in the striatum in vivo. Furthermore, when administered to the substantia nigra of rats, nitrated α-synuclein caused PD-like motor dysfunctions, such as reduced locomotion and motor asymmetry, however unmodified α-synuclein had significantly less severe behavioral effects.Conclusions/SignificanceOur results provide evidence that α-synuclein, principally in its nitrated form, induce DA neuron death and may be a major factor in the etiology of PD.

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Section: Discussionmentioning

confidence: 99%

Nitrated α-Synuclein Induces the Loss of Dopaminergic Neurons in the Substantia Nigra of Rats

Xiang

et al. 2010

PLoS ONE

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“…With the exception of one study, which delineated a prooxidant effect of vitamin A in the substantia nigra and striatum at clinical doses (103), all of the other studies showed either neutral or positive correlations with cognitive dysfunction. Engelhart et al examined whether high plasma levels of vitamins A and E together were associated with lower prevalence of cognitive decline.…”

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confidence: 90%

Reactive Oxygen Species in the Regulation of Synaptic Plasticity and Memory

Massaad

Klann

2011

Antioxidants & Redox Signaling

493

350

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The brain is a metabolically active organ exhibiting high oxygen consumption and robust production of reactive oxygen species (ROS). The large amounts of ROS are kept in check by an elaborate network of antioxidants, which sometimes fail and lead to neuronal oxidative stress. Thus, ROS are typically categorized as neurotoxic molecules and typically exert their detrimental effects via oxidation of essential macromolecules such as enzymes and cytoskeletal proteins. Most importantly, excessive ROS are associated with decreased performance in cognitive function. However, at physiological concentrations, ROS are involved in functional changes necessary for synaptic plasticity and hence, for normal cognitive function. The fine line of role reversal of ROS from good molecules to bad molecules is far from being fully understood. This review focuses on identifying the multiple sources of ROS in the mammalian nervous system and on presenting evidence for the critical and essential role of ROS in synaptic plasticity and memory. The review also shows that the inability to restrain either age-or pathology-related increases in ROS levels leads to opposite, detrimental effects that are involved in impairments in synaptic plasticity and memory function.

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“…Indeed, we have experimentally demonstrated that vitamin A (retinol palmitate) at clinical doses induced anxiety-related behavior in adult Wistar rats. Furthermore, we have observed decreased locomotory and exploratory activities performed by such animals in an open field apparatus [9][10][11][12][13][14][15]. Recently, it was reported decreased brain metabolism in patients subjected to daily retinoid therapy [16] and, more concerning, increased mortality rates among vitamin supplements users even when ingesting low daily vitamin A doses (mainly as retinol palmitate) [17].…”

Section: Introductionmentioning

confidence: 84%

Total and Mitochondrial Nitrosative Stress, Decreased Brain-Derived Neurotrophic Factor (BDNF) Levels and Glutamate Uptake, and Evidence of Endoplasmic Reticulum Stress in the Hippocampus of Vitamin A-Treated Rats

et al. 2010

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Vitamin A supplementation has caused concern among public health researchers due to its ability in decreasing life quality from acute toxicological effects to increasing mortality rates among vitamin supplement users. For example, it was described cognitive decline (i.e. irritability, anxiety, and depression) in patients subjected to long-term vitamin A therapy, as occurs in cancer treatment. However, the mechanism by which vitamin A affects mammalian cognition is not completely understood. Then, we performed the present work to investigate the effects of vitamin A supplementation at clinical doses (1,000-9,000 IU/kg day(-1)) for 28 days on rat hippocampal nitrosative stress levels (both total and mitochondrial), bioenergetics states, brain-derived neurotrophic factor (BDNF), alpha- and beta-synucleins, BiP and dopamine receptor 2 (D2 receptor) contents, and glutamate uptake. We observed mitochondrial impairment regarding respiratory chain function: increased complex I-III, but decreased complex IV enzyme activity. Also, decreased BDNF levels were observed in vitamin A-treated rats. The present data demonstrates, at least in part, that mitochondrial dysfunction and decreased BDNF and D2 receptors levels, as well as decreased glutamate uptake may take an important role in the mechanism behind the previously reported cognitive disturbances associated to vitamin A supplementation.

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Evaluation of the effects of vitamin A supplementation on adult rat substantia nigra and striatum redox and bioenergetic states: Mitochondrial impairment, increased 3-nitrotyrosine and α-synuclein, but decreased D2 receptor contents

Cited by 22 publications

References 52 publications

Nitrated α-Synuclein Induces the Loss of Dopaminergic Neurons in the Substantia Nigra of Rats

Nitrated α-Synuclein Induces the Loss of Dopaminergic Neurons in the Substantia Nigra of Rats

Reactive Oxygen Species in the Regulation of Synaptic Plasticity and Memory

Total and Mitochondrial Nitrosative Stress, Decreased Brain-Derived Neurotrophic Factor (BDNF) Levels and Glutamate Uptake, and Evidence of Endoplasmic Reticulum Stress in the Hippocampus of Vitamin A-Treated Rats

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