A novel synthetic activator of Nurr1 induces dopaminergic gene expression and protects against 6-hydroxydopamine neurotoxicity in vitro

Hammond, Sean L.; Safe, Stephen; Tjalkens, Ronald B.

doi:10.1016/j.neulet.2015.09.015

Cited by 41 publications

(41 citation statements)

References 28 publications

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“…After a comparative analysis, C-DIM12 (higher affinity for Nurr1) has the most potent neuroprotective activity and anti-inflammatory effect in MPTP-lesioned rat model of PD [53]. It could enhance the expressions of Nurr1 and Nurr1-regulated proteins such as TH and DAT, and Nurr1-mediated recruitment of CoREST and the NF-κB-mediated inflammatory genes expression are suppressed in SN [53–55]. …”

Section: Nurr1-activating Compoundsmentioning

confidence: 99%

Nurr1‐Based Therapies for Parkinson's Disease

Dong

et al. 2016

CNS Neurosci Ther

104

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Previous studies have documented that orphan nuclear receptor Nurr1 (also known as NR4A2) plays important roles in the midbrain dopamine (DA) neuron development, differentiation and survival. Furthermore, it has been reported that the defects in Nurr1 are associated with Parkinson’s disease (PD). Thus, Nurr1 might be a potential therapeutic target for PD. Emerging evidence from in vitro and in vivo studies has recently demonstrated that Nurr1-activating compounds and Nurr1 gene therapy are able not only to enhance DA neurotransmission but also to protect DA neurons from cell injury induced by environmental toxin or microglia-mediated neuroinflammation. Moreover, modulators that interact with Nurr1 or regulate its function, such as retinoid X receptor, cyclic AMP-responsive element-binding protein, glial cell line-derived neurotrophic factor and Wnt/β-catenin pathway have the potential to enhance the effects of Nurr1-based therapies in PD. This review highlights the recent progress in preclinical studies of Nurr1-based therapies and discusses the outlook of this emerging therapy as a promising new generation of PD medication.

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Section: Nurr1-activating Compoundsmentioning

confidence: 99%

Nurr1‐Based Therapies for Parkinson's Disease

Dong

et al. 2016

CNS Neurosci Ther

104

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“…Because of their dopaminergic properties [1], rat dopaminergic N27 cells have been widely used in in vitro models for PD studies [1,3]. They have also been used in studies seeking to understand problems such as neurotoxicity, oxidative stress, and histone deacetylase (HDAC) and other molecular pathways [4][5][6]. While there have been studies on synaptophysin signaling in N27 cells, the electrophysiological effects of graphene on N27 cells are currently unknown.…”

Section: Introductionmentioning

confidence: 99%

Viability of Neural Cells on 3D Printed Graphene Bioelectronics

et al. 2019

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Parkinson’s disease (PD) is the second most common neurodegenerative disease in the United States after Alzheimer’s disease (AD). To help understand the electrophysiology of these diseases, N27 neuronal cells have been used as an in vitro model. In this study, a flexible graphene-based biosensor design is presented. Biocompatible graphene was manufactured using a liquid-phase exfoliation method and bovine serum albumin (BSA) for further exfoliation. Raman spectroscopy results indicated that the graphene produced was indeed few-layer graphene (FLG) with ID/IGGraphene= 0.11. Inkjet printing of this few-layer graphene ink onto Kapton polyimide (PI) followed by characterization via scanning electron microscopy (SEM) showed an average width of ≈868 µm with a normal thickness of ≈5.20 µm. Neuronal cells were placed on a thermally annealed 3D printed graphene chip. A live–dead cell assay was performed to prove the biosensor biocompatibility. A cell viability of approximately 80% was observed over 96 h, which indicates that annealed graphene on Kapton PI substrate could be used as a neuronal cell biosensor. This research will help us move forward with the study of N27 cell electrophysiology and electrical signaling.

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“…Nurr1 activation has been shown to confer neuroprotection ( Barneda-Zahonero et al, 2012;Hammond and Safe, 2015;Hammond et al, 2018) and is anti-inflammatory through its ability to suppress nuclear factor kappaB (NFκB) activation (Saijo et al, 2009;De Miranda et al, 2015), yet there are no reports on whether Nurr1 induction is neuroprotective in models of ischemic stroke. Ischemia induced Nurr1 mRNA upregulation has been reported in global ischemia in gerbils (Honkaniemi and Sharp, 1996) and in rats with permanent middle cerebral artery occlusion (Honkaniemi et al, 1997), whereas protein levels of Nurr1 were shown to be decreased in mice subjected to transient ischemia (Erdö et al, 2004).…”

Section: Introductionmentioning

confidence: 99%

HX600, a synthetic agonist for RXR-Nurr1 heterodimer complex, prevents ischemia-induced neuronal damage

Loppi

Kołosowska

Kärkkäinen

et al. 2018

Brain, Behavior, and Immunity

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Ischemic stroke is amongst the leading causes of death and disabilities. The available treatments are suitable for only a fraction of patients and thus novel therapies are urgently needed. Blockage of one of the cerebral arteries leads to massive and persisting inflammatory reaction contributing to the nearby neuronal damage. Targeting the detrimental pathways of neuroinflammation has been suggested to be beneficial in conditions of ischemic stroke. Nuclear receptor 4A-family (NR4A) member Nurr1 has been shown to be a potent modulator of harmful inflammatory reactions, yet the role of Nurr1 in cerebral stroke remains unknown. Here we show for the first time that an agonist for the dimeric transcription factor Nurr1/retinoid X receptor (RXR), HX600, reduces microglia expressed proinflammatory mediators and prevents inflammation induced neuronal death in in vitro co-culture model of neurons and microglia. Importantly, HX600 was protective in a mouse model of permanent middle cerebral artery occlusion and alleviated the stroke induced motor deficits. Along with the anti-inflammatory capacity of HX600 in vitro, treatment of ischemic mice with HX600 reduced ischemia induced Iba-1, p38 and TREM2 immunoreactivities, protected endogenous microglia from ischemia induced death and prevented leukocyte infiltration. These anti-inflammatory functions were associated with reduced levels of brain lysophosphatidylcholines (lysoPCs) and acylcarnitines, metabolites related to proinflammatory events. These data demonstrate that HX600 driven Nurr1 activation is beneficial in ischemic stroke and propose that targeting Nurr1 is a novel candidate for conditions involving neuroinflammatory component.

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A novel synthetic activator of Nurr1 induces dopaminergic gene expression and protects against 6-hydroxydopamine neurotoxicity in vitro

Cited by 41 publications

References 28 publications

Nurr1‐Based Therapies for Parkinson's Disease

Nurr1‐Based Therapies for Parkinson's Disease

Viability of Neural Cells on 3D Printed Graphene Bioelectronics

HX600, a synthetic agonist for RXR-Nurr1 heterodimer complex, prevents ischemia-induced neuronal damage

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