Hypothyroidism Causes Endoplasmic Reticulum Stress in Adult Rat Hippocampus: A Mechanism Associated with Hippocampal Damage.

Alejandra Paola Torres-Manzo,Margarita Franco-Colín,Edgar Cano-Europa,Marisol Pineda-Reynoso,Vanessa Blas-Valdivia

doi:10.1155/2018/2089404

Alejandra Paola Torres-Manzo, Margarita Franco-Colín + Show 3 more

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https://doi.org/10.1155/2018/2089404

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Abstract

Thyroid hormones (TH) are essential for hippocampal neuronal viability in adulthood, and their deficiency causes hypothyroidism, which is related to oxidative stress events and neuronal damage. Also, it has been hypothesized that hypothyroidism causes a glucose deprivation in the neuron. This study is aimed at evaluating the temporal participation of the endoplasmic reticulum stress (ERE) in hippocampal neurons of adult hypothyroid rats and its association with the oxidative stress events. Adult Wistar male rats were divided into euthyroid and hypothyroid groups. Thyroidectomy with parathyroid gland reimplementation caused hypothyroidism at three weeks postsurgery. Oxidative stress, redox environment, and antioxidant enzyme markers, as well as the expression of the ERE through the pathways of PERK, ATF6, and IRE1, were evaluated at the 3rd and 4th weeks postsurgery. We found a rise in ROS and nitrite production; also, catalase increased and glutathione peroxidase diminished their activities. These events promote an enhancement of the lipoperoxidation, as well as of γ-GT, myeloperoxidase, and caspase 3 activities. With respect to ERE, there were ATF6, IRE1, and GADD153 overexpressions with a reduction in mitochondrial activity and GSH2/GSSG ratio. We conclude that the endoplasmic reticulum stress might play a pivotal role in the activation of hypothyroidism-induced hippocampal cell death.

Highlights

Hypothyroidism is a clinical condition in which thyroid hormone (TH) release of the thyroid gland is low, and it is not enough to satisfy the demand of the tissues [1]
Increased oxidant products were not successfully neutralized by antioxidant enzymes catalase, superoxide dismutase (SOD), glutathione peroxidase (GPX), and glutathione reductase (GR) (Figures 3(a)–3(d), resp.), since only catalase activity increased at the third week and GPX activity was diminished at both times evaluated
Besides that this is one of the most accepted mechanisms of hypothyroidism-induced hippocampal neuronal death, it cannot be the only one, or at least, not the primary inducer for several reasons, one of which is that other works have found that glutamate synthesis and release are diminished in hypothyroidism [31, 32]

Summary

Introduction

Hypothyroidism is a clinical condition in which thyroid hormone (TH) release of the thyroid gland is low, and it is not enough to satisfy the demand of the tissues [1]. TH deficiencies lead to a broad spectrum of clinical manifestations, including neurologic symptoms like memory impairment, difficulty concentrating, and depression [2, 3]. These alterations are directly linked with the hippocampus, which is especially sensitive to thyroid hormone deprivation [4,5,6]. The biological events mentioned above are probably an activation consequence of several mechanisms; one of them can be the endoplasmic reticulum stress (ERE). The ERE triggers lead to ER overload of misfolded and not folded proteins and the consequent activation of the UPR[11]

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