Hypothyroidism Induces Interleukin-1-Dependent Autophagy Mechanism as a Key Mediator of Hippocampal Neuronal Apoptosis and Cognitive Decline in Postnatal Rats

Mishra, Juhi; Vishwakarma, Jitendra; Malik, Rafat; Gupta, Keerti; Pandey, Rukmani; Maurya, Shailendra Kumar; Garg, Asmita; Shukla, Manoj Kumar; Chattopadhyay, Naibedya; Bandyopadhyay, Sanghamitra

doi:10.1007/s12035-020-02178-9

Cited by 21 publications

(17 citation statements)

References 80 publications

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“…The hippocampus is a brain region susceptible to neuronal damage due to onset-adult hypothyroidism. The mechanism involved the change in neurotransmission, particularly the glutamatergic pathways ( Alva-Sánchez et al, 2009 ; Giné et al, 2010 ; Sánchez-Huerta et al, 2012 ) that causes oxidative and endoplasmic reticulum stresses ( Torres-Manzo et al, 2018 ), neuroinflammation and autophagy ( Mishra et al, 2021 ). Nevertheless, it is crucial to develop a treatment to avoid the neuronal damage due to this disease.…”

Section: Discussionmentioning

confidence: 99%

“…Activation of apoptotic mitogen-activated protein kinase (MAPK) p38-p53 pathway in astroglia increased IL-1β, IL6, and TNFα with a higher expression of COX2 ( Nam et al, 2018 ). Neuroinflammation caused by hypothyroidism is associated with hippocampal autophagy ( Mishra et al, 2021 ). Our results support this hypothesis because PERK/eIF2α activation promotes autophagosome elongation and maturation ( Zheng et al, 2019 ).…”

Section: Discussionmentioning

confidence: 99%

“…Recently, it has been demonstrated that hypothyroidism promotes neuroinflammation and dysregulation of glia-neuron communication. This pathophysiological situation induces hippocampal apoptosis through autophagy ( Mishra et al, 2021 ).…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2021

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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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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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

et al. 2021

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“…The microglia from hippocampus showed sex-biased differences in the expression of TH-regulated genes. Fold change ± 1.5, p value 0.05, and FDR 0.05. n = 3 males and n = 4 females autophagy and neuronal apoptosis in postnatal rats that accounts for cognitive impairment [104].…”

Section: Thyroid Hormone In Neurodegenerative and Psychiatric Diseasesmentioning

confidence: 99%

Thyroid hormone: sex-dependent role in nervous system regulation and disease

Baksi¹,

Pradhan

2021

Biol Sex Differ

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Thyroid hormone (TH) regulates many functions including metabolism, cell differentiation, and nervous system development. Alteration of thyroid hormone level in the body can lead to nervous system-related problems linked to cognition, visual attention, visual processing, motor skills, language, and memory skills. TH has also been associated with neuropsychiatric disorders including schizophrenia, bipolar disorder, anxiety, and depression. Males and females display sex-specific differences in neuronal signaling. Steroid hormones including testosterone and estrogen are considered to be the prime regulators for programing the neuronal signaling in a male- and female-specific manner. However, other than steroid hormones, TH could also be one of the key signaling molecules to regulate different brain signaling in a male- and female-specific manner. Thyroid-related diseases and neurological diseases show sex-specific incidence; however, the molecular mechanisms behind this are not clear. Hence, it will be very beneficial to understand how TH acts in male and female brains and what are the critical genes and signaling networks. In this review, we have highlighted the role of TH in nervous system regulation and disease outcome and given special emphasis on its sex-specific role in male and female brains. A network model is also presented that provides critical information on TH-regulated genes, signaling, and disease.

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“…Interestingly, it has been recently reported that, in a rat model of developmental hypothyroidism, obtained by treating rats from gestation to adulthood with methimazole, autophagy was stimulated in the hippocampal neurons that regulate cognitive functions, with induction of neuroinflammation and impairment of learning and memory capacity This hippocampal neuronal dysfunction could be improved by T4 treatment [ 208 ].…”

Section: Thyroid Hormones and Mammalian Brain Developmentmentioning

confidence: 99%

Involvement of Thyroid Hormones in Brain Development and Cancer

Schiera

Liegro

2021

Cancers

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The development and maturation of the mammalian brain are regulated by thyroid hormones (THs). Both hypothyroidism and hyperthyroidism cause serious anomalies in the organization and function of the nervous system. Most importantly, brain development is sensitive to TH supply well before the onset of the fetal thyroid function, and thus depends on the trans-placental transfer of maternal THs during pregnancy. Although the mechanism of action of THs mainly involves direct regulation of gene expression (genomic effects), mediated by nuclear receptors (THRs), it is now clear that THs can elicit cell responses also by binding to plasma membrane sites (non-genomic effects). Genomic and non-genomic effects of THs cooperate in modeling chromatin organization and function, thus controlling proliferation, maturation, and metabolism of the nervous system. However, the complex interplay of THs with their targets has also been suggested to impact cancer proliferation as well as metastatic processes. Herein, after discussing the general mechanisms of action of THs and their physiological effects on the nervous system, we will summarize a collection of data showing that thyroid hormone levels might influence cancer proliferation and invasion.

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Hypothyroidism Induces Interleukin-1-Dependent Autophagy Mechanism as a Key Mediator of Hippocampal Neuronal Apoptosis and Cognitive Decline in Postnatal Rats

Cited by 21 publications

References 80 publications

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

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

Thyroid hormone: sex-dependent role in nervous system regulation and disease

Involvement of Thyroid Hormones in Brain Development and Cancer

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