The orphan nuclear receptor Nurr1 agonist amodiaquine mediates neuroprotective effects in 6-OHDA Parkinson’s disease animal model by enhancing the phosphorylation of P38 mitogen-activated kinase but not PI3K/AKT signaling pathway

Kambey, Piniel Alphayo; Guo, Xinwen; Abdulrahman, Ayanlaja Abiola; Kanwore, Kouminin; Nadeem, Iqra; Wu, Jiao; Gao, Dianshuai

doi:10.1007/s11011-021-00670-2

Cited by 11 publications

(13 citation statements)

References 63 publications

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“…Interestingly, none of the analogs showed lower transcriptional activity than compound 1 as the remaining analogs 10 , 11 , 15 , 16 , 17 , 18 revealed comparable activity that ranged from 105% to 110%, respectively (Figure B). Recent reports , suggest that the antimalarial drug amodiaquine (AQ) may serve as a Nurr1 ligand. Therefore, we tested the ability of AQ to activate transcription in our Nurr1/NBRE-luciferase reporter system, both alone and in combination with bexarotene or a subset of our more potent RXR agonists using both U87 and HEK cells.…”

Section: Resultsmentioning

confidence: 99%

Evaluating Novel RXR Agonists That Induce ApoE and Tyrosine Hydroxylase in Cultured Human Glioblastoma Cells

Mallick

Marshall

Wagner

et al. 2021

ACS Chem. Neurosci.

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There is considerable interest in identifying effective and safe drugs for neurodegenerative disorders. Cell culture and animal model work have demonstrated that modulating gene expression through RXR-mediated pathways may mitigate or reverse cognitive decline. However, because RXR is a dimeric partner for several transcription factors, activating off-target transcription is a concern with RXR ligands (rexinoids). This off-target gene modulation leads to unwanted side effects that can include low thyroid function and significant hyperlipidemia. There is a need to develop rexinoids that have binding specificity for subsets of RXR heterodimers, to drive desired gene modulation, but that do not induce spurious effects. Herein, we describe experiments in which we analyze a series of novel and previously reported rexinoids for their ability to modulate specific gene pathways implicated in neurodegenerative disorders employing a U87 cell culture model. We demonstrate that, compared to the FDA-approved rexinoid bexarotene (1), several of these compounds are equally or more effective at stimulating gene expression via LXREs or Nurr1/NBREs and are superior at inducing ApoE and/or tyrosine hydroxylase (TH) gene and protein expression, including analogs 8, 9, 13, 14, 20, 23, and 24, suggesting a possible therapeutic role for these compounds in Alzheimer's or Parkinson's disease (PD). A subset of these potent RXR agonists can synergize with a presumed Nurr1 ligand and antimalarial drug (amodiaquine) to further enhance Nurr1/NBREs-directed transcription. This novel discovery has potential clinical implications for treatment of PD since it suggests that the combination of an RXR agonist and a Nurr1 ligand can significantly enhance RXR-Nurr1 heterodimer activity and drive enhanced therapeutic expression of the TH gene to increase endogenous synthesis of dopamine. These data indicate that is it possible and prudent to develop novel rexinoids for testing of gene expression and side effect profiles for use in potential treatment of neurodegenerative disorders, as individual rexinoids can have markedly different gene expression profiles but similar structures.

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Section: Resultsmentioning

confidence: 99%

Evaluating Novel RXR Agonists That Induce ApoE and Tyrosine Hydroxylase in Cultured Human Glioblastoma Cells

Mallick

Marshall

Wagner

et al. 2021

ACS Chem. Neurosci.

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“…First, Nurr1 activation by AQ has been linked to neuroprotection. Activation of Nurr1 by AQ leads to the generation of neurons from cortical [ 42 ] and hippocampal [ 42 , 47 , 48 ] neural precursor cells, enhances short-and long-term memory, and improves cognitive deficits in mouse models of Parkinson’s [ 49 , 50 ] and Alzheimer’s disease [ 51 ]. Second, AQ is known to be a selective agonist for Nurr1 with no effect on other members of the NR4A family (Nur77 and NOR1) [ 49 ].…”

Section: Discussionmentioning

confidence: 99%

Nurr1 Is Not an Essential Regulator of BDNF in Mouse Cortical Neurons

Abdollahi

Fahnestock

2022

IJMS

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Nurr1 and brain-derived neurotrophic factor (BDNF) play major roles in cognition. Nurr1 regulates BDNF in midbrain dopaminergic neurons and cerebellar granule cells. Nurr1 and BDNF are also highly expressed in the cerebral cortex, a brain area important in cognition. Due to Nurr1 and BDNF tissue specificity, the regulatory effect of Nurr1 on BDNF in different brain areas cannot be generalized. The relationship between Nurr1 and BDNF in the cortex has not been investigated previously. Therefore, we examined Nurr1-mediated BDNF regulation in cortical neurons in activity-dependent and activity-independent states. Mouse primary cortical neurons were treated with the Nurr1 agonist, amodiaquine (AQ). Membrane depolarization was induced by KCl or veratridine and reversed by nimodipine. AQ and membrane depolarization significantly increased Nurr1 (p < 0.001) and BDNF (pAQ < 0.001, pKCl < 0.01) as assessed by real-time qRT-PCR. However, Nurr1 knockdown did not affect BDNF gene expression in resting or depolarized neurons. Accordingly, the positive correlation between Nurr1 and BDNF expression in AQ and membrane depolarization experiments does not imply co-regulation because Nurr1 knockdown did not affect BDNF gene expression in resting or depolarized cortical neurons. Therefore, in contrast to midbrain dopaminergic neurons and cerebellar granule cells, Nurr1 does not regulate BDNF in cortical neurons.

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“…Further purification was performed by column chromatography (n-hexane/EtOAc 3:1) to yield 22 as a colorless solid (32 mg, 11%). 1 1H-Indole-3-carboxylic Acid Ethyl Ester (23). H 2 SO 4 (conc., 1 mL) was added to a solution of 19 (200 mg, 1.24 mmol, 1.00 equiv) in ethanol (20 mL).…”

Section: ■ Conclusionmentioning

confidence: 99%

“…Novel Nurr1 ligands are hence needed to probe the therapeutic potential of Nurr1 in neurodegeneration and other pathologies. Importantly, while the moderately potent Nurr1 agonist AQ (1) has been successfully used to probe Nurr1 activation in vivo, 5,13,23,24 no potent inverse Nurr1 agonist that blocks the nuclear receptor's high basal activity is available to date.…”

Section: ■ Introductionmentioning

confidence: 99%

“…The free carboxylate 19, the aldehyde 20, and the ketones 21 and 22 were inactive on Nurr1, indicating that the ester was essential. Alternative aliphatic esters (ethyl (23) and tert-butyl (24)) were, however, neither tolerated, and the phenyl ester analogue 25 even exhibited Nurr1 agonistic activity. Such a shift from inverse agonism to agonism had already occurred in N-phenyl derivative 17, suggesting an important role of phenyl modification in causing agonist activity.…”

Section: ■ Introductionmentioning

confidence: 99%

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Development and Profiling of Inverse Agonist Tools for the Neuroprotective Transcription Factor Nurr1

et al. 2021

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The ligand-sensing transcription factor nuclear receptor related 1 (Nurr1) evolves as an appealing target to treat neurodegenerative diseases. Despite its therapeutic potential observed in various rodent models, potent modulators for Nurr1 are lacking as pharmacological tools. Here, we report the structure–activity relationship and systematic optimization of indole-based inverse Nurr1 agonists. Optimized analogues decreased the receptor’s intrinsic transcriptional activity by up to more than 90% and revealed preference for inhibiting Nurr1 monomer activity. In orthogonal cell-free settings, we detected displacement of NCoRs and disruption of the Nurr1 homodimer as molecular modes of action. The inverse Nurr1 agonists reduced the expression of Nurr1-regulated genes in T98G cells, and treatment with an inverse Nurr1 agonist mimicked the effect of Nurr1 silencing on interleukin-6 release from LPS-stimulated human astrocytes. The indole-based inverse Nurr1 agonists valuably extend the toolbox of Nurr1 modulators to further probe the role of Nurr1 in neuroinflammation, cancer, and beyond.

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The orphan nuclear receptor Nurr1 agonist amodiaquine mediates neuroprotective effects in 6-OHDA Parkinson’s disease animal model by enhancing the phosphorylation of P38 mitogen-activated kinase but not PI3K/AKT signaling pathway

Cited by 11 publications

References 63 publications

Evaluating Novel RXR Agonists That Induce ApoE and Tyrosine Hydroxylase in Cultured Human Glioblastoma Cells

Evaluating Novel RXR Agonists That Induce ApoE and Tyrosine Hydroxylase in Cultured Human Glioblastoma Cells

Nurr1 Is Not an Essential Regulator of BDNF in Mouse Cortical Neurons

Development and Profiling of Inverse Agonist Tools for the Neuroprotective Transcription Factor Nurr1

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