Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2018 Jun:186:176-185.
doi: 10.1016/j.pharmthera.2018.01.007. Epub 2018 Feb 9.

Thyroid hormone and the brain: Mechanisms of action in development and role in protection and promotion of recovery after brain injury

Yan-Yun Liu  1 , Gregory A Brent  2
Affiliations
Review

Thyroid hormone and the brain: Mechanisms of action in development and role in protection and promotion of recovery after brain injury

Yan-Yun Liu et al. Pharmacol Ther. 2018 Jun.

Abstract

Thyroid hormone (TH) is essential for normal brain development and may also promote recovery and neuronal regeneration after brain injury. TH acts predominantly through the nuclear receptors, TH receptor alpha (THRA) and beta (THRB). Additional factors that impact TH action in the brain include metabolism, activation of thyroxine (T4) to triiodothyronine (T3) by the enzyme 5'-deiodinase Type 2 (Dio2), inactivation by the enzyme 5-deiodinase Type 3 (Dio3) to reverse T3 (rT3), which occurs in glial cells, and uptake by the Mct8 transporter in neurons. Traumatic brain injury (TBI) is associated with inflammation, metabolic alterations and neural death. In clinical studies, central hypothyroidism, due to hypothalamic and pituitary dysfunction, has been found in some individuals after brain injury. TH has been shown, in animal models, to be protective for the damage incurred from brain injury and may have a role to limit injury and promote recovery. Although clinical trials have not yet been reported, findings from in vitro and in vivo models inform potential treatment strategies utilizing TH for protection and promotion of recovery after brain injury.

Keywords: Deiodinase; Neuronal protection; Thyroid hormone; Thyroid hormone receptor; Thyroid hormone transport; Traumatic brain injury.

PubMed Disclaimer

Conflict of interest statement

Conflicts of interest

The authors declare that there are no conflicts of interest.

Figures

Figure 1
Figure 1. Model of Neurons and Glial Cells With Pathways of Thyroid Hormone Metabolism and Uptake
Thyroid hormone action in the brain requires activation of thyroxine (T4) to the active triiodothyronine (T3), by the 5′-deiodinase 2 (Dio2), contained in glial cells. T3 uptake into neurons is mediated by specific transporters, Mct8 and Oatp1c1, present in both humans and mice, but humans appear most dependent on Mct8.
Figure 2
Figure 2. Model of the Pathways Activated by Brain Injury and Potential Sites of Thyroid Hormone Action
Brain injury is associated with edema, mitochondrial-mediated apoptosis, and local hypoxia, and in response promotion of cell survival and neurogenesis. Thyroid hormone (TH) has demonstrated actions on these pathways with potential mechanisms, as are shown in this figure, and treatment may reduce edema, inflammation and enhance recovery. SERCA, Ca2+-ATPase; SR, Sarcoplasmic reticulum; ROS, Reactive oxygen species; NO, Nitric oxide; AQP4, Aquaporin 4; TH, Thyroid hormone; THRA, Thyroid hormone receptor alpha; SVZ, Subventricular zone; SGZ, Subgranular zone
See this image and copyright information in PMC

References

    1. Accorroni A, Giorgi FS, Donzelli R, Lorenzini L, Prontera C, Saba A, Vergallo A, Tognoni G, Siciliano G, Baldacci F, Bonuccelli U, Clerico A, Zucchi R. Thyroid hormone levels in the cerebrospinal fluid correlate with disease severity in euthyroid patients with Alzheimer7s disease. Endocrine. 2017;55:981–984. - PubMed
    1. Alkemade A, Friesema EC, Kalsbeek A, Swaab DF, Visser TJ, Fliers E. Expression of thyroid hormone transporters in the human hypothalamus. J Clin Endocrinol Metab. 2011;96:E967–971. - PubMed
    1. Alvarez-Mora MI, Rodriguez-Revenga L, Madrigal I, Garcia-Garcia F, Duran M, Dopazo J, Estivill X, Mila M. Deregulation of key signaling pathways involved in oocyte maturation in FMR1 premutation carriers with Fragile X-associated primary ovarian insufficiency. Gene. 2015;571:52–57. - PubMed
    1. Anderson GW, Larson RJ, Oas DR, Sandhofer CR, Schwartz HL, Mariash CN, Oppenheimer JH. Chicken ovalbumin upstream promoter-transcription factor (COUP-TF) modulates expression of the Purkinje cell protein-2 gene. A potential role for COUP-TF in repressing premature thyroid hormone action in the developing brain. J Biol Chem. 1998;273:16391–16399. - PubMed
    1. Barca-Mayo O, Liao XH, Alonso M, Di Cosmo C, Hernandez A, Refetoff S, Weiss RE. Thyroid hormone receptor alpha and regulation of type 3 deiodinase. Mol Endocrinol. 2011;25:575–583. - PMC - PubMed

Publication types

Substances