# Thyroid Hormone and Neuronal Protection

> **NIH VA I01** · VA GREATER LOS ANGELES HEALTHCARE SYSTEM · 2024 · —

## Abstract

Thyroid hormone (TH) is essential for normal brain development and promotes recovery
and neuronal regeneration after brain injury. TH acts in the brain predominantly through
the nuclear receptor, TH receptor alpha (THRA). Additional factors that impact TH
action in the brain including 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 across the cell membrane by the Mct8 transporter in neurons.
Traumatic brain injury (TBI) is associated with inflammation, metabolic alterations and
neuronal death. In clinical studies, serum levels of T4 and T3, as well as TH levels in
the brain, are reduced. We have utilized rodent models of TBI to demonstrate that
treatment with T4, 1 hour after injury (selected to model a practical time of
administration after injury), is protective, reduces edema, and promotes neuronal
recovery. We have identified a similar protective effect of TH in an in vitro model of
neuronal injury from hypoxia as well as neuronal inflammation. We will study the
mechanism of TH protection from neuronal injury, utilizing in vivo mouse models of TBI.
We have preliminary data identifying genes whose expression is impacted by hypoxic
neuronal injury and those that are normalized by TH treatment. We will characterize
these genes in the brains of mice after injury to identify specific pathways and locations
influenced by TH treatment with a whole genome approach. Hypoxic injury increases
histone methylation in neurons and this is reduced by T3 treatment. We believe that this
is an important mechanism for T3 protection after injury. We will also identify T3-
stimulated pathways that activate neural regeneration. We have also shown that injury
impairs glial cell proliferation and migration, partially restored by T4 treatment. We will
utilize in vivo rodent models of TBI and in vitro models to identify the actions of TH on
glial cells and the resulting balance of pro- and anti- inflammatory pathways. The
response to TH therapy will include assessment of the brain lesions by imaging and
brain region-specific patterns of gene expression. TH reduction in brain edema and cell
death, and promotion of neuronal regeneration, should provide a beneficial effect after
brain injury. These studies should provide guidance for clinical strategies to use TH,
likely with other agents that are anti-inflammatory, to reduce the impact of brain injury
and promote recovery.

## Key facts

- **NIH application ID:** 10806042
- **Project number:** 2I01BX001966-09A1
- **Recipient organization:** VA GREATER LOS ANGELES HEALTHCARE SYSTEM
- **Principal Investigator:** GREGORY A BRENT
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2024
- **Award amount:** —
- **Award type:** 2
- **Project period:** 2014-01-01 → 2028-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10806042

## Citation

> US National Institutes of Health, RePORTER application 10806042, Thyroid Hormone and Neuronal Protection (2I01BX001966-09A1). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10806042. Licensed CC0.

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