Nurr1 modulation mediates neuroprotective effects of statins

Abstract

The ligand-sensing transcription factor Nurr1 emerges as a promising therapeutic target for neurodegenerative pathologies but Nurr1 ligands for functional studies and therapeutic validation are lacking. Here we report pronounced Nurr1 modulation by statins for which clinically relevant neuroprotective effects have been demonstrated. Several statins directly affected Nurr1 activity in cellular and cell-free settings with low micromolar to sub-micromolar potencies. Simvastatin exhibited anti-inflammatory effects in astrocytes which were abrogated by Nurr1 knockdown. Differential gene expression analysis in native and Nurr1 silenced cells revealed strong proinflammatory effects of Nurr1 knockdown while simvastatin treatment induced several neuroprotective mechanisms via Nurr1, for example, in energy utilization and reduced apoptosis. These findings suggest Nurr1 involvement in the well-documented but mechanistically elusive neuroprotection by statins.

Scaffold Hopping from Amodiaquine to Novel Nurr1 Agonist Chemotypes via Microscale Analogue Libraries

“…In a cell‐free time‐resolved fluorescence resonance energy transfer (HTRF) assay, 3 j (5 μM, 10 μM) diminished dimerization of the Tb 3+ ‐cryptate‐labeled Nurr1 LBD and the GFP‐labeled Nurr1 LBD (Figure 2c). Similar effects on Nurr1 homodimerization were observed with Nurr1 agonistic statins [31] thus confirming direct Nurr1 modulation by 3 j . In the Gal4‐Nurr1 reporter gene assay, 3 j already exceeded the potency of AQ (EC 50 36 μM) and chloroquine (CQ, EC 50 47 μM) highlighting the 5‐(4‐chlorophenyl)furan‐2‐ylmethylamine substituent as attractive novel Nurr1 ligand moiety.…”

“…Further in vitro characterization of the new Nurr1 agonist chemotype 4 e additionally revealed activation of human full‐length Nurr1 in reporter gene assays for the human Nurr1 response elements NBRE, NurRE and DR5 (Figure 4a), and the HTRF assay confirmed direct Nurr1 modulation by 4 e (Figure 4b) as observed by decreased dimerization despite a weak non‐specific baseline shift. The fact that 4 e activated the Nurr1 homodimer (NurRE) although the HTRF assay showed decreased Nurr1 dimerization in presence of 4 e indicates, however, that also other molecular mechanisms than dimerization involve in the Nurr1 agonism of 4 e as it has been observed for other Nurr1 ligands [24,31,33] . Further studies will be needed to elucidate the co‐regulatory network and molecular mechanisms driving Nurr1 activation by ligands entirely.…”

“…The fact that 4 e activated the Nurr1 homodimer (NurRE) although the HTRF assay showed decreased Nurr1 dimerization in presence of 4 e indicates, however, that also other molecular mechanisms than dimerization involve in the Nurr1 agonism of 4 e as it has been observed for other Nurr1 ligands. [ 24 , 31 , 33 ] Further studies will be needed to elucidate the co‐regulatory network and molecular mechanisms driving Nurr1 activation by ligands entirely.…”