Elunetirom, a brain-targeted TRβ prodrug, promotes neuronal plasticity and mitochondrial biogenesis-related signaling in primary neuronal cultures

Major depressive disorder and bipolar depression are disabling illnesses associated with impaired neuroplasticity, mitochondrial dysfunction, and altered cellular bioenergetics. Available pharmacotherapies often have delayed onset, incomplete efficacy, and limited effects on underlying plasticity and energetic systems. Non-selective thyroid hormone therapies provide evidence that enhancing central thyroid hormone signaling may improve depressive symptoms, but systemic cardiovascular, skeletal, and metabolic effects limit their broader use. Rapid-acting treatments such as esketamine and psychedelics further support neuroplasticity as a therapeutic strategy, although psychotomimetic, hallucinogenic, and implementation burdens may constrain widespread use. Elunetirom is a brain-targeted, fatty acid amide hydrolase-sensitive prodrug of LL-340001, a potent thyroid hormone receptor activator as demonstrated in transfected cell-line and brain-slice target-engagement assays. We evaluated elunetirom and LL-340001 in primary cortical and mature hippocampal neuronal cultures. LL-340001 increased MAP-2-positive neuron number, neurite length, branching, and neurite extremities in immature cortical neurons. In mature hippocampal neurons, elunetirom rapidly increased neurite network and synapse number within 24 hours, with effects persisting through 72 hours, while LL-340001 preserved synapse number following amyloid-{beta}1-42 challenge. LL-340001 also increased nuclear PGC-1 and NRF2, the number of functional mitochondria measured by MitoTracker, and ATP content. Pharmacologic inhibition indicated that the LL-340001-induced increase in cortical MAP-2-positive neuron number was sensitive to TrkB inhibition but not 5-HT2A antagonism. Together, these findings indicate that elunetirom and LL- 340001 engage complementary neuroplasticity and mitochondrial biogenesis-related programs in neuronal systems and support further investigation of brain-targeted thyromimetic signaling as a mechanistically differentiated approach for major depressive disorder and bipolar depression.