The Role of Thyroid Hormones as Inductors of Oxidative Stress and Neurodegeneration

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Abstract

Reactive oxygen species (ROS) are oxidizing agents amply implicated in tissue damage. ROS production is inevitably linked to ATP synthesis in most cells, and the rate of production is related to the rate of cell respiration. Multiple antioxidant mechanisms limit ROS dispersion and interaction with cell components, but, when the balance between ROS production and scavenging is lost, oxidative damage develops. Many traits of aging are related to oxidative damage by ROS, including neurodegenerative diseases. Thyroid hormones (THs) are a major factor controlling metabolic and respiratory rates in virtually all cell types in mammals. The general metabolic effect of THs is a relative acceleration of the basal metabolism that includes an increase of the rate of both catabolic and anabolic reactions. THs are related to oxidative stress not only by their stimulation of metabolism but also by their effects on antioxidant mechanisms. Thyroid dysfunction increases with age, so changes in THs levels in the elderly could be a factor affecting the development of neurodegenerative diseases. However, the relationship is not always clear. In this review, we analyze the participation of thyroid hormones on ROS production and oxidative stress, and the way the changes in thyroid status in aging are involved in neurodegenerative diseases.

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Mitochondria in homeostasis of reactive oxygen species in cell, tissues, and organism.

Petr Ježek, Lydie Plecitá-Hlavatá (2005)

The recent knowledge on mitochondria as the substantial source of reactive oxygen species, namely superoxide and hydrogen peroxide efflux from mitochondria, is reviewed, as well as nitric oxide and subsequent peroxynitrite generation in mitochondria and their effects. The reactive oxygen species formation in extramitochondrial locations, in peroxisomes, by cytochrome P450, and NADPH oxidase reaction, is also briefly discussed. Conditions are pointed out under which mitochondria represent the major ROS source for the cell: higher percentage of non-phosphorylating and coupled mitochondria, in vivo oxygen levels leading to increased intensity of the reverse electron transport in the respiratory chain, and nitric oxide effects on the redox state of cytochromes. We formulate hypotheses on the crucial role of ROS generated in mitochondria for the whole cell and organism, in concert with extramitochondrial ROS and antioxidant defense. We hypothesize that a sudden decline of mitochondrial ROS production converts cells or their microenvironment into a "ROS sink" represented by the instantly released excessive capacity of ROS-detoxification mechanisms. A partial but immediate decline of mitochondrial ROS production may be triggered by activation of mitochondrial uncoupling, specifically by activation of recruited or constitutively present uncoupling proteins such as UCP2, which may counterbalance the mild oxidative stress.

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Oxidative stress in Parkinson's disease: a mechanism of pathogenic and therapeutic significance.

Yong Huang, Chun-wu Zhou, Serge Przedborski (2008)

Parkinson's disease (PD) is a common adult-onset neurodegenerative disorder. Typically PD is a sporadic neurological disorder, and over time affected patients see their disability growing and their quality of life declining. Oxidative stress has been hypothesized to be linked to both the initiation and the progression of PD. Preclinical findings from both in vitro and in vivo experimental models of PD suggest that the neurodegenerative process starts with otherwise healthy neurons being hit by some etiological factors, which sets into motion a cascade of deleterious events. In these models initial molecular alterations in degenerating dopaminergic neurons include increased formation of reactive oxygen species, presumably originating from both inside and outside the mitochondria. In the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of PD, time-course experiments suggest that oxidative stress is an early event that may directly kill some of the dopaminergic neurons. In this model it seems that oxidative stress may play a greater role in the demise of dopaminergic neurons indirectly by activating intracellular, cell death-related, molecular pathways. As the neurodegenerative process evolves in the MPTP mouse model, indices of neuroinflammation develop, such as microglial activation. The latter increases the level of oxidative stress to which the neighboring compromised neurons are subjected to, thereby promoting their demise. However, these experimental studies have also shown that oxidative stress is not the sole deleterious factor implicated in the death of dopaminergic neurons. Should a similar multifactorial cascade underlie dopaminergic neuron degeneration in PD, then the optimal therapy for this disease may have to rely on a cocktail of agents, each targeting a different critical component of this hypothesized pathogenic cascade. If correct, this may be a reason why neuroprotective trials using a single agent, such as an antioxidant, have thus far generated disappointing results.

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Oxidative stress in blood in Alzheimer's disease and mild cognitive impairment: a meta-analysis.

M Zabel, O Ghribi, R. Squitti … (2013)

Abnormal oxidative stress is an established feature of Alzheimer's disease, but clinical trials aiming to reduce oxidative stress have not yet proven an effective therapy for dementia patients. The purpose of this review is to systematically analyze available data describing markers of oxidative stress and antioxidants in blood from subjects with Alzheimer's disease or those with mild cognitive impairment to highlight potential interactions between peripheral redox changes and central nervous system pathology and contribute to the design of future clinical study. PubMed, SCOPUS and Web of Science were systematically queried to collect studies which have evaluated markers of oxidative stress, levels of antioxidants, copper, transferrin and ceruloplasmin levels in blood from subjects with Alzheimer's disease and matched controls. After application of quality measures, results were aggregated in a random effects analysis. We found that markers of lipid peroxidation are elevated in blood in Alzheimer's disease and in mild cognitive impairment, copper metabolism is dysregulated and total antioxidant capacity is decreased. While surprisingly none of the major antioxidative enzymes are significantly decreased, non-enzymatic antioxidants in blood (particularly uric acid, vitamins A, E and C, α- and β-carotene) are significantly decreased. There is significant oxidative damage in peripheral blood early in the process of neurodegeneration. We propose that clinical studies assessing cognitive outcomes after antioxidant therapy tailor interventions to individual patients' deficiencies and confirm an improvement in an appropriate serological marker of oxidative stress. This strategy may be most effectively applied in a clinical trial of primary prevention. © 2013.

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Author and article information

Journal

Journal ID (nlm-ta): Oxid Med Cell Longev

Journal ID (iso-abbrev): Oxid Med Cell Longev

Journal ID (publisher-id): OXIMED

Title: Oxidative Medicine and Cellular Longevity

Publisher: Hindawi Publishing Corporation

ISSN (Print): 1942-0900

ISSN (Electronic): 1942-0994

Publication date (Print): 2013

Publication date (Electronic): 9 December 2013

Volume: 2013

Electronic Location Identifier: 218145

Affiliations

Departamento de Fisiología, Escuela Nacional de Ciencias Biológicas, IPN. Prol. Carpio y Plan de Ayala, s/n, 11340 México City, DF, Mexico

Author notes

*J. Pacheco-Rosado: jprosado@ 123456hotmail.com

Academic Editor: Sathyasaikumar V. Korrapati

Article

DOI: 10.1155/2013/218145

PMC ID: 3872098

PubMed ID: 24386502

SO-VID: 1c6c8c3c-bec8-43bb-b770-55e7902820cf

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This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

History

Date received : 18 September 2013

Date accepted : 8 November 2013

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The Role of Thyroid Hormones as Inductors of Oxidative Stress and Neurodegeneration

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Most cited references 141

Mitochondria in homeostasis of reactive oxygen species in cell, tissues, and organism.

Oxidative stress in Parkinson's disease: a mechanism of pathogenic and therapeutic significance.

Oxidative stress in blood in Alzheimer's disease and mild cognitive impairment: a meta-analysis.

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