Gallic Acid Prevents the Oxidative and Endoplasmic Reticulum Stresses in the Hippocampus of Adult-Onset Hypothyroid Rats

Thyroid hormone is essential for hippocampal redox environment and neuronal viability in adulthood, where its deficiency causes hypothyroidism related to oxidative and endoplasmic reticulum stresses in the hippocampus, resulting in neuronal death. One option of treatment is antioxidants; however, they must be transported across the blood-brain barrier. Gallic acid is a polyphenol that meets these criteria. Thus, this study aimed to prove that the neuroprotective mechanism of GA is associated with the prevention of oxidative and endoplasmic reticulum stresses in the hippocampus of adult-onset hypothyroid rats. Male Wistar rats were divided into euthyroid (n = 20) and hypothyroid groups (n = 20). Thyroidectomy with parathyroid gland reimplementation caused hypothyroidism. Each group was subdivided into two: vehicle and 50 mg/kg/d of gallic acid. 3 weeks after thyroidectomy, six animals of each group were euthanized, and the hippocampus was dissected to evaluate oxidative and endoplasmic reticulum stress markers. The rest of the animals were euthanized after 4 weeks of treatment for histological analysis of the hippocampus. The results showed that hypothyroidism increased lipid peroxidation, reactive oxygen species, and nitrites; it also increased endoplasmic reticulum stress by activating the inositol-requiring enzyme-1α (IRE1α) pathway, the protein kinase RNA-like endoplasmic reticulum kinase (PERK) and activated transcription factor 6α (ATF6α) pathways associated with a proapoptotic state that culminates in hippocampal neuronal damage. Meanwhile, the hypothyroid rat treated with gallic acid reduced oxidative stress and increased endoplasmic reticulum-associated degradation (ERAD) through IRE1α and ATF6. Also, the gallic acid treatment prevented the Bax/BCl2 ratio from increasing and the overexpression of p53 and caspase 12. This treatment in hypothyroid animals was associated with the neuronal protection observed in the hippocampus. In conclusion, gallic acid prevents hypothyroidism-induced hippocampal damage associated with oxidative and endoplasmic reticulum stresses.

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

Oxidative Medicine and Cellular Longevity ◽

10.1155/2018/2089404 ◽

2018 ◽

Vol 2018 ◽

pp. 1-12 ◽

Cited By ~ 2

Author(s):

Alejandra Paola Torres-Manzo ◽

Margarita Franco-Colín ◽

Vanessa Blas-Valdivia ◽

Marisol Pineda-Reynoso ◽

Edgar Cano-Europa

Keyword(s):

Oxidative Stress ◽

Endoplasmic Reticulum ◽

Endoplasmic Reticulum Stress ◽

Hippocampal Neurons ◽

Neuronal Damage ◽

Glucose Deprivation ◽

Male Rats ◽

Mitochondrial Activity ◽

Hippocampal Damage ◽

Nitrite Production

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.

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Excessive training is associated with endoplasmic reticulum stress but not apoptosis in the hypothalamus of mice

Applied Physiology Nutrition and Metabolism ◽

10.1139/apnm-2016-0542 ◽

2017 ◽

Vol 42 (4) ◽

pp. 354-360 ◽

Cited By ~ 5

Author(s):

Ana Paula Pinto ◽

Alisson Luiz da Rocha ◽

Bruno Cesar Pereira ◽

Luciana da Costa Oliveira ◽

Gustavo Paroschi Morais ◽

...

Keyword(s):

Endoplasmic Reticulum ◽

Endoplasmic Reticulum Stress ◽

Downhill Running ◽

Stress Markers ◽

Caspase 12 ◽

Tnf Α

Downhill running-based overtraining model increases the hypothalamic levels of IL-1β, TNF-α, SOCS3, and pSAPK-JNK. The aim of the present study was to verify the effects of 3 overtraining protocols on the levels of BiP, pIRE-1 (Ser724), pPERK (Thr981), pelF2α (Ser52), ATF-6, GRP-94, caspase 4, caspase 12, pAKT (Ser473), pmTOR (Ser2448), and pAMPK (Thr172) proteins in the mouse hypothalamus. The mice were randomized into the control, overtrained by downhill running (OTR/down), overtrained by uphill running (OTR/up), and overtrained by running without inclination (OTR) groups. After the overtraining protocols (i.e., at the end of week 8), hypothalamus was removed and used for immunoblotting. The OTR/down group exhibited increased levels of all of the analyzed endoplasmic reticulum stress markers in the hypothalamus at the end of week 8. The OTR/up and OTR groups exhibited increased levels of BiP, pIRE-1 (Ser724), and pPERK (Thr981) in the hypothalamus at the end of week 8. There were no significant differences in the levels of caspase 4, caspase 12, pAKT (Ser473), pmTOR (Ser2448), and pAMPK (Thr172) between the experimental groups at the end of week 8. In conclusion, the 3 overtraining protocols increased the endoplasmic reticulum stress at the end of week 8.

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Endoplasmic Reticulum Stress Contributes to Nociception via Neuroinflammation in a Murine Bone Cancer Pain Model

Anesthesiology ◽

10.1097/aln.0000000000003078 ◽

2020 ◽

Vol 132 (2) ◽

pp. 357-372 ◽

Cited By ~ 2

Author(s):

Yanting Mao ◽

Chenchen Wang ◽

Xinyu Tian ◽

Yulin Huang ◽

Ying Zhang ◽

...

Keyword(s):

Endoplasmic Reticulum ◽

Endoplasmic Reticulum Stress ◽

Cancer Pain ◽

Inflammatory Mediators ◽

Bone Cancer ◽

Intrathecal Administration ◽

Bone Cancer Pain ◽

Stress Markers ◽

Mechanical Threshold ◽

Tnf Α

Abstract Editor’s Perspective What We Already Know about This Topic What This Article Tells Us That Is New Background Prolonged endoplasmic reticulum stress has been identified in various diseases. Inflammatory mediators, which have been shown to induce endoplasmic reticulum stress in several studies, have been suggested to serve as the important modulators in pain development. In this study, the authors hypothesized that the endoplasmic reticulum stress triggered by inflammatory mediators contributed to pain development. Methods The authors used a male mouse model of bone cancer pain. The control mice were intrathecally injected with tumor necrosis factor-α (TNF-α) and lipopolysaccharide, the bone cancer pain mice were intrathecally injected with the endoplasmic reticulum stress inhibitors 4-PBA and GSK2606414. The nociceptive behaviors, endoplasmic reticulum stress markers, and inflammatory mediators were assessed. Results Increased expression of the p-RNA-dependent protein kinase-like endoplasmic reticulum kinase and p-eukaryotic initiation factor 2α were found in the spinal neurons during bone cancer pain, along with upregulation of inflammatory mediators (TNF-α, interleukin 1β, and interleukin 6). Intrathecal administration of TNF-α or lipopolysaccharide increased the expression of endoplasmic reticulum stress markers in control mice. Inhibition of endoplasmic reticulum stress by intrathecal administration of 4-PBA (baseline vs. 3 h: 0.34 ± 0.16 g vs. 1.65 ± 0.40 g in paw withdrawal mechanical threshold, 8.00 ± 1.20 times per 2 min vs. 0.88 ± 0.64 times per 2 min in number of spontaneous flinches, P < 0.001, n = 8) or GSK2606414 (baseline vs. 3 h: 0.37 ± 0.08 g vs. 1.38 ± 0.11 g in paw withdrawal mechanical threshold, 8.00 ± 0.93 times per 2 min vs. 3.25 ± 1.04 times per 2 min in number of spontaneous flinches, P < 0.001, n = 8) showed time- and dose-dependent antinociception. Meanwhile, decreased expression of inflammatory mediators (TNF-α, interleukin 1β, and interleukin 6), as well as decreased activation of astrocytes in the spinal cord, were found after 4-PBA or GSK2606414 treatment. Conclusions Inhibition of inflammatory mediator–triggered endoplasmic reticulum stress in spinal neurons attenuates bone cancer pain via modulation of neuroinflammation, which suggests new approaches to pain relief.

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The value of endoplasmic reticulum stress markers (GRP78 and CHOP) in the diagnosis of acute mesenteric ischemia

The American Journal of Emergency Medicine ◽

10.1016/j.ajem.2018.06.033 ◽

2019 ◽

Vol 37 (4) ◽

pp. 596-602 ◽

Cited By ~ 1

Author(s):

Senol Ardic ◽

Aysegul Gumrukcu ◽

Ozgen Gonenc Cekic ◽

Mehmet Erdem ◽

Goksen Derya Reis Kose ◽

...

Keyword(s):

Endoplasmic Reticulum ◽

Endoplasmic Reticulum Stress ◽

Mesenteric Ischemia ◽

Acute Mesenteric Ischemia ◽

Stress Markers

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114 ENDOPLASMIC RETICULUM (ER) STRESS IN HYPOXIA-INDUCED DIABETES MELLITUS MODEL

Reproduction Fertility and Development ◽

10.1071/rdv28n2ab114 ◽

2016 ◽

Vol 28 (2) ◽

pp. 187

Author(s):

C. Ahn ◽

D. Lee ◽

K. P. Kim ◽

M. H. Lee ◽

E.-B. Jeung

Keyword(s):

Endoplasmic Reticulum ◽

Endoplasmic Reticulum Stress ◽

Er Stress ◽

Pancreatic Beta Cells ◽

Hypoxic Condition ◽

Protein Translation ◽

Ion Concentration ◽

Cellular Stress Response ◽

Stress Markers ◽

Calbindin D9k

Endoplasmic reticulum (ER) regulates calcium ion concentration as a reservoir in the cell. ER stress is a cellular stress response related to the endoplasmic reticulum. At the initial stage of ER stress, ER tries to restore normal function by halting protein translation, degrading misfolded proteins, and increasing production of chaperones involved in protein folding. If ER fails to restore ER stress, ER stress can lead cells to apoptosis. To study the signaling between ER stress and calcium channels under ER-stressed circumstances, we designed a hypoxia-induced diabetic model. Nine-week-old male mice were chosen, maintained under hypoxic condition under 10% O2, 5% CO2 for 10 days, and the expression of ER stress markers and calcium channel gene expression were examined by real-time PCR. By maintaining hypoxic condition, the mice showed high glucose levels. Under this diabetic condition, in pancreatic beta cells, ER stress markers were elevated. This tendency showed an increase in calbindin-D9k KO mice. Chaperones such as calreticulin and calnexin were decreased, but in calbindin-D9k KO mice chaperone calnexin was not decreased. Interestingly, the calbindin-D9k KO normoxia mice showed increased glucose level compared with wild-type normoxia mice. Also, calnexin expression of pancreas was decreased in calbindin-D9k KO normoxia mice. This result indicates that pancreas cells were under endoplasmic reticulum stress. Taken together, calbindin may play an important role in endoplasmic reticulum stress in pancreas. This work was supported by the National Research Foundation of Korea (NRF) grant of Korean government (MEST) (No. 2013-010514).

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