Thyroid hormones are of fundamental importance for brain development and essential factors to warrant brain functions throughout life. Their actions are mediated by binding to specific intracellular and membranous receptors regulating genomic and non-genomic mechanisms in neurons and populations of glial cells, respectively. Among others, mechanisms include the regulation of neuronal plasticity processes, stimulation of angiogenesis and neurogenesis as well modulating the dynamics of cytoskeletal elements and intracellular transport processes. These mechanisms overlap with those that have been identified to enhance recovery of lost neurological functions during the first weeks and months after ischemic stroke. Stimulation of thyroid hormone signaling in the postischemic brain might be a promising therapeutic strategy to foster endogenous mechanisms of repair. Several studies have pointed to a significant association between thyroid hormones and outcome after stroke. With this review, we will provide an overview on functions of thyroid hormones in the healthy brain and summarize their mechanisms of action in the developing and adult brain. Also, we compile the major thyroid-modulated molecular pathways in the pathophysiology of ischemic stroke that can enhance recovery, highlighting thyroid hormones as a potential target for therapeutic intervention.

Thyroid Hormones in the Brain and Their Impact in Recovery Mechanisms After Stroke.

Brain to periphery in acute ischemic stroke: Mechanisms and clinical significance.

Thyroid hormone is essential for brain development and brain function in the adult During development, thyroid hormone acts in a spatial and temporal-specific manner to regulate the expression of genes essential for normal neural cell differentiation, migration, and myelination In the adult brain, thyroid hormone is important for maintaining normal brain function Thyroid hormone excess, hyperthyroidism, and thyroid hormone deficiency, hypothyroidism, are associated with disordered brain function, including depression, memory loss, impaired cognitive function, irritability, and anxiety Adequate thyroid hormone levels are required for normal brain function Thyroid hormone acts through a cascade of signaling components: activation and inactivation by deiodinase enzymes, thyroid hormone membrane transporters, and nuclear thyroid hormone receptors Additionally, the hypothalamic-pituitary-thyroid axis, with negative feedback of thyroid hormone on thyrotropin-releasing hormone (TRH) and thyroid-stimulating hormone (TSH) secretion, regulates serum thyroid hormone levels in a narrow range Animal and human studies have shown both systemic and local reduction in thyroid hormone availability in neurologic disease and after brain trauma Treatment with thyroid hormone and selective thyroid hormone analogs has resulted in a reduction in injury and improved recovery This article will describe the thyroid hormone signal transduction pathway in the brain and the role of thyroid hormone in the aging brain, neurologic diseases, and the protective role when administered after traumatic brain injury © 2021 American Physiological Society Compr Physiol 11:1-21, 2021

The Role of Thyroid Hormone in Neuronal Protection.

Toxicological studies show that exposure to disinfection byproducts, including trihalomethanes (THMs), negatively affects thyroid function; however, few epidemiological studies have explored this link. This study included 2233 adults (ages ≥20 years) from the 2007-2008 National Health and Nutrition Examination Survey (NHANES) who were measured for blood THM concentrations [chloroform (TCM), bromodichloromethane (BDCM), dibromochloromethane (DBCM), or bromoform (TBM)] and serum thyroid function biomarkers [thyroid-stimulating hormone, free thyroxine (FT4), total thyroxine (TT4), free triiodothyronine (FT3), total triiodothyronine (TT3), thyroid peroxidase antibody (TPOAb), and thyroglobulin antibody (TgAb)]. Multivariable linear regression models showed positive associations between blood TCM, BDCM, and total THMs (the sum of all four THMs) concentrations and serum FT4, whereas inverse associations were found between blood DBCM and total brominated THM (Br-THM; the sum of BDCM, DBCM, and TBM) concentrations and serum TT3 (all p < 0.05). Besides, positive associations were observed between blood TCM concentrations and FT4/FT3 ratio, between BDCM, DBCM, and Br-THM concentrations and TT4/TT3 ratio, and between DBCM and Br-THM concentrations and FT3/TT3 ratio (all p < 0.05). Blood THM concentrations were unrelated to the serum levels of thyroid autoantibodies TgAb or TPOAb. In summary, exposure to THMs was associated with altered serum biomarkers of thyroid function but not with thyroid autoimmunity among U.S. adults.

Relationship between Blood Trihalomethane Concentrations and Serum Thyroid Function Measures in U.S. Adults.

Neurodegenerative diseases are characterized by chronic neuronal and/or glial cell loss, while traumatic injury is often accompanied by the acute loss of both. Multipotent neural stem cells (NSCs) in the adult mammalian brain spontaneously proliferate, forming neuronal and glial progenitors that migrate toward lesion sites upon injury. However, they fail to replace neurons and glial cells due to molecular inhibition and the lack of pro-regenerative cues. A major challenge in regenerative biology therefore is to unveil signaling pathways that could override molecular brakes and boost endogenous repair. In physiological conditions, thyroid hormone (TH) acts on NSC commitment in the subventricular zone, and the subgranular zone, the two largest NSC niches in mammals, including humans. Here, we discuss whether TH could have beneficial actions in various pathological contexts too, by evaluating recent data obtained in mammalian models of multiple sclerosis (MS; loss of oligodendroglial cells), Alzheimer's disease (loss of neuronal cells), stroke and spinal cord injury (neuroglial cell loss). So far, TH has shown promising effects as a stimulator of remyelination in MS models, while its role in NSC-mediated repair in other diseases remains elusive. Disentangling the spatiotemporal aspects of the injury-driven repair response as well as the molecular and cellular mechanisms by which TH acts, could unveil new ways to further exploit its pro-regenerative potential, while TH (ant)agonists with cell type-specific action could provide safer and more target-directed approaches that translate easier to clinical settings.

/pdf/thyroid-hormone-and-neural-stem-cells-repair-potential-2ew5eny0gf.pdf

Thyroid Hormone and Neural Stem Cells: Repair Potential Following Brain and Spinal Cord Injury.

Previous studies on the association between thyroid hormones and prognosis of acute ischemic stroke (AIS) reported conflicting results. We conducted a meta-analysis to assess the prognostic value of thyroid hormones in AIS. The PubMed, EMBASE, and Cochrane library databases were searched through May 12, 2017 to identify eligible studies on this subject. Out of 2,181 studies retrieved, 11 studies were finally included with a total number of 3,936 acute stroke patients for analysis. Odds ratio (OR) for predicting poor outcome or standardized mean difference (SMD) of thyroid hormone levels with 95% confidence intervals (95% CI) obtained from the studies were pooled using Review Manager 5.3. From the results, in AIS, patients with a poor outcome had lower levels of triiodothyronine (T3) and higher thyroxine (T4). Pooled OR confirmed the same association. Our study provides statistical evidence supporting the utility of thyroid hormone levels in prognosis of acute stroke.

/pdf/prognostic-value-of-thyroid-hormones-in-acute-ischemic-4finebgi6e.pdf

Prognostic value of thyroid hormones in acute ischemic stroke – a meta analysis

A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has been fixed in the paper.

/pdf/author-correction-prognostic-value-of-thyroid-hormones-in-5fjlvu8zis.pdf

Author Correction: Prognostic value of thyroid hormones in acute ischemic stroke - a meta analysis.

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Prognostic value of thyroid hormones in acute ischemic stroke – a meta analysis

Author Correction: Prognostic value of thyroid hormones in acute ischemic stroke - a meta analysis.