The pathophysiology of brain damage that is common to
ischemia-reperfusion injury and
brain trauma include disodered neuronal and glial cell energetics, intracellular
acidosis,
calcium toxicity, extracellular excitotoxic
glutamate accumulation, and dysfunction of the cytoskeleton and endoplasmic reticulum. The principal
thyroid hormones, 3,5,3'-triiodo-l-thyronine (T(3)) and
l-thyroxine (T(4)), have non-genomic and genomic actions that are relevant to repair of certain features of the pathophysiology of brain damage. The
hormone can non-genomically repair intracellular H(+) accumulation by stimulation of the
Na(+)/H(+) exchanger and can support desirably low [Ca(2+)](i.c.) by activation of plasma membrane Ca(2+)-
ATPase.
Thyroid hormone non-genomically stimulates astrocyte
glutamate uptake, an action that protects both glial cells and neurons. The
hormone supports the integrity of the microfilament cytoskeleton by its effect on actin. Several
proteins linked to
thyroid hormone action are also neuroprotective. For example, the
hormone stimulates expression of the seladin-1 gene whose gene product is anti-apoptotic and is potentially protective in the setting of neurodegeneration.
Transthyretin (TTR) is a serum
transport protein for T(4) that is important to blood-brain barrier transfer of the
hormone and TTR also has been found to be neuroprotective in the setting of
ischemia. Finally, the interesting
thyronamine derivatives of T(4) have been shown to protect against ischemic brain damage through their ability to induce
hypothermia in the intact organism. Thus,
thyroid hormone or
hormone derivatives have experimental promise as
neuroprotective agents.