Thyroid Hormone Protects Primary Cortical Neurons Exposed to Hypoxia By Reducing DNA Methylation and Apoptosis

[helvella]

As we read more and more about the fine detail of how thyroid hormones act, as in this paper, we see how subtle and complex this is.

At the same time, the endocrinologists seem to be making their blunt tools ever blunter. I have a nasty suspicion that they would be waiting for TSH to rise sufficiently before condoning use of thyroid hormones (of any sort). While the patient's brain deteriorates.

Endocrinology. 2019 May 16. pii: en.2019-00125. doi: 10.1210/en.2019-00125. [Epub ahead of print]

Thyroid Hormone Protects Primary Cortical Neurons Exposed to Hypoxia By Reducing DNA Methylation and Apoptosis.

Li J1,2, Abe K1, Milanesi A1, Liu YY1, Brent GA1.

Author information

1 Molecular Endocrinology Laboratory, VA Greater Los Angeles Healthcare System, Endocrinology Division, Departments of Medicine and Physiology, David Geffen School of Medicine at UCLA.

2 Department of Endocrinology, Union Hospital, Fujian Medical University, Fuzhou, Fujian, China.

Abstract

Traumatic Brain Injury (TBI) is associated with disruption of cerebral blood flow leading to localized brain hypoxia. Thyroid hormone (TH) treatment, administered shortly after injury, has been shown to promote neural protection in rodent TBI models. The mechanism of TH protection, however, is not established. We used mouse primary cortical neurons to investigate the effectiveness and possible pathways of T3-promoted cell survival after exposure to hypoxic injury. Cultured primary cortical neurons were exposed to hypoxia (0.2% oxygen) for 7 hours with or without T3 (5 nM). T3 treatment enhanced DNA 5-hydroxymethylcytosine (5-hmc) levels and attenuated the hypoxia-induced increase in DNA 5-methylcytosine (5-mc). In the presence of T3, mRNA expression of Tet family genes was increased and DNA methyltransferases, (Dnmt) 3a and Dnmt3b, were downregulated, compared to conditions in the absence of T3. These T3-induced changes decreased hypoxia-induced DNA de novo methylation, which reduced hypoxia-induced neuronal damage and apoptosis. We utilized RNA-seq to characterize T3-regulated genes in cortical neurons under hypoxic conditions and identified 22 genes that were upregulated and 15 genes that were downregulated. Krupple-like factor 9 (KLF9), a multifunctional transcription factor that plays a key role in CNS development, was highly upregulated by T3 treatment in hypoxic conditions. Knockdown of the KLF9 gene resulted in early apoptosis and abolished the beneficial role of T3 in neuronal survival. KLF9 mediates, in part, the neuronal protective role of T3. T3 treatment reduces hypoxic damage, although pathways that reduce DNA methylation and apoptosis, remains to be elucidated.

Copyright © 2019 Endocrine Society.

PMID: 31095291

DOI: 10.1210/en.2019-00125

ncbi.nlm.nih.gov/pubmed/310...

[crimple]

thanks for posting. I hope that even the small amount of T3 I am taking will help preserve my brain function, such as it is!

[JGBH]

Thanks for posting this interesting but worrying link! Does it mean that not having enough T3 in the body but mostly in the brain, as in having below range T3 through lack of adequate conversion (or any other cause) could lead to brain hypoxia?

[helvella Administrator in reply to JGBH]

That is not how I read it. Rather, that if you suffered a brain injury, the hypoxia that resulted from that injury, might be made less damaging by giving T3 treatment.

I have been reading about thyroid issues far too long to make any assumptions, though. So I could be wrong.

[JGBH in reply to helvella]

It's what I hoped... and thought in a way. Hypoxia would have to be brought on by a brain injury, then T3 could help. I just panicked.. Thanks for answering.

[dtate2016]

Great article! I know someone who’s been diagnosed with borderline thyroid problems hypothyroid problems for over 25 years and untreated. She has taken all manner of Prozac like drugs, been in therapy for more than three years with no progress, and is generally in constant turmoil mentally and emotionally. I truly believe this article underlines the idea that the root cause of her problems is in lack of treatment for Hashimoto’s.

A little thyroid hormone would go such a long ways towards helping her live a happy life but I will never be able to get her to read this article. And she rejects my constant urging to go to the doctor and endocrinologist here in USA. And yet here is the beginning of proof.

Thanks again for the wonderful article.

[humanbean]

I have a nasty suspicion that they would be waiting for TSH to rise sufficiently before condoning use of thyroid hormones (of any sort). While the patient's brain deteriorates.

I can well imagine doctors insisting on a TSH test before treating a patient with TBI with thyroid hormones no matter what the guidelines say, just because they've been brainwashed themselves. If the result comes back with TSH under 20 doctors will be too scared to treat in case it puts a greater stress on an already sick patient. After all, the patient might show signs of hyperthyroidism! They might have a heart attack! They might break a bone! They'll be sued for millions! Panic! Panic! Panic!