Dopamine neuron induction and the neuroprotective effects of thyroid hormone derivatives

Abstract

Parkinson's disease (PD) is a neurodegenerative disease characterized by progressive movement disturbances caused by the selective loss of dopamine (DA) neurons in the substantia nigra. Despite the identification of the causal mechanisms underlying the pathogenesis of PD, effective treatments remain elusive. In this study, we observed that a low level of fetal bovine serum (FBS) effectively induced DA neurons in rat neural precursor cells (NPCs) by enhancing nuclear receptor-related 1 protein (NURR1) expression. Among the various components of FBS, the thyroid hormones triiodothyronine (T3) and thyroxine (T4) were identified as key factors for the induction of DA neurons. Since an overdose of thyroid hormones can cause hyperthyroidism, we synthesized several thyroid hormone derivatives that can partially activate thyroid hormone receptors and induce the complete differentiation of NPCs into DA neurons. Two derivatives (#3 and #9) showed positive effects on the induction and maturation of DA neurons without showing significant affinity for the thyroid hormone receptor. They also effectively protected and restored DA neurons from neurotoxic insults. Taken together, these observations demonstrate that thyroid hormone derivatives can strongly induce DA neuron differentiation while avoiding excessive thyroid stimulation and might therefore be useful candidates for PD treatment.