Characterizing the effects of NR4A modulation in neuroinflammation in vitro

The ligand-activated transcription factor Nurr1 (NR4A2) has emerged as a promising target in the context of neurodegenerative diseases such as Parkinson’s disease, multiple sclerosis and Alzheimer’s disease. Despite its high potential, supported by genetic studies and observations in human patients, comprehensive evaluation of Nurr1 modulation as therapeutic concept and the receptor’s role in neurobiology remains a significant challenge as potent Nurr1 modulators are rare and also target the highly related subfamily members Nur77 (NR4A1) and NOR1 (NR4A3).

We followed a chemogenomic approach to explore Nurr1 and probed the hypothesis that Nurr1 agonism mediates neuroprotective and anti-neuroinflammatory effects. We used a set of six structurally diverse NR4A modulators, including three agonists and three inverse agonists, and determined compound effects on neuron homeostasis, neuronal survival and neuroinflammation in vitro. Single- and coculture models of immortalized dopaminergic neurons and macrophages under proinflammatory or neurotoxic conditions revealed sensitizing effects of inverse NR4A agonists towards neuronal insults but no conclusive neuroprotection by NR4A agonists. As transcriptional analyses pointed to highly variable NR4A expression patterns in the neuronal cell lines, the observed lack of efficacy may be due to opposing effects of Nur77 and Nurr1 possibly masking beneficial effects of NR4A activators. Nurr1 agonists with improved selectivity over the related NR4A receptors are hence needed to validate the promising clinical findings on Nurr1 in vitro and advance the receptor as therapeutic target.