Nurr1 as an Emerging Therapeutic Target for Parkinson’s Disease

Abstract

Parkinson's disease (PD) is a progressive neurodegenerative disease in which midbrain dopaminergic neurons are destroyed. In the current state of PD treatments, pharmacological treatments are mostly symptomatic and become ineffective with time. They have severe side effects, including dyskinesia. In view of this, developing treatments based on mechanisms of action and/or disease modification remains an unmet clinical need. We hypothesize that Nurr1, a nuclear orphan receptor, can be a molecular target for neuroprotective therapeutic development for Parkinson's disease because of its dual role in dopaminergic neurons development and maintenance as well as their protection from inflammation-induced degeneration. Moreover, it has been reported that mutations in Nurr1 are linked to Parkinson's disease. Nurr1-activating compounds have recently been demonstrated to enhance DA neurotransmission as well as protect DA neurons from microglia-mediated neuroinflammation and environmental toxin damage. Furthermore, modulators targeting Nurr1, such as 4-amino-7-chloroquinoline derivatives and retinoid X receptors, can enhance the effects of Nurr1-based therapies. Therefore, the aim of this project is to evaluate the efficacy of bexarotene and amodiaquine on activating Nurr1 receptor in SHSY-5Y neuroblastoma cells by using tyrosine hydroxylase (TH) promoter- luciferase assay. Here we show unsuccessful increase in Nurr1 activity in response to both amodiaquine and bexarotene with ( EC50 = 4.86 uM and EC50 = 2.95 mM, respectively). These novel ligands require more experiments to determine their biological significance in Nurr1 activation. It is advantageous to reposition or reprofile drugs in this manner since it reduces the time and investment involved in drug discovery, development, and safety since target and pharmacokinetic profiles have been determined in advance.