Molecular Insights into NR4A2(Nurr1): an Emerging Target for Neuroprotective Therapy Against Neuroinflammation and Neuronal Cell Death

Jakaria, Md.; Haque, Md. Ezazul; Cho, Duk-Yeon; Azam, Shofiul; Kim, In-Su; Choi, Dong‐Kug

doi:10.1007/s12035-019-1487-4

Cited by 83 publications

(70 citation statements)

References 154 publications

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“…Unfortunately, their therapeutics are disappointing and limited to symptomatic treatment. However, targeting the underlying pathobiology of the NDDs would disrupt disease progression and improve the conditions [199]. Herein, several GPCRs and their agonists or antagonists under screening or approved for AD, PD, MS, or HD, have been discussed.…”

Section: Discussionmentioning

confidence: 99%

“…The potential of these compounds in terms of acting on GPCRs needs to be studied [5,6,200]. Several recent studies reported that nuclear receptor subfamily 4 group A member 2 [199], NACHT, LRR, and PYD domains containing protein 3 [201], and glutamate receptors [202] have great potential in neuroprotective therapy. The correlation between GPCRs and these target molecules would be a fascinating area of research.…”

Section: Discussionmentioning

confidence: 99%

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G-Protein-Coupled Receptors in CNS: A Potential Therapeutic Target for Intervention in Neurodegenerative Disorders and Associated Cognitive Deficits

Azam

Haque

Jakaria

et al. 2020

Cells

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Neurodegenerative diseases are a large group of neurological disorders with diverse etiological and pathological phenomena. However, current therapeutics rely mostly on symptomatic relief while failing to target the underlying disease pathobiology. G-protein-coupled receptors (GPCRs) are one of the most frequently targeted receptors for developing novel therapeutics for central nervous system (CNS) disorders. Many currently available antipsychotic therapeutics also act as either antagonists or agonists of different GPCRs. Therefore, GPCR-based drug development is spreading widely to regulate neurodegeneration and associated cognitive deficits through the modulation of canonical and noncanonical signals. Here, GPCRs’ role in the pathophysiology of different neurodegenerative disease progressions and cognitive deficits has been highlighted, and an emphasis has been placed on the current pharmacological developments with GPCRs to provide an insight into a potential therapeutic target in the treatment of neurodegeneration.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

G-Protein-Coupled Receptors in CNS: A Potential Therapeutic Target for Intervention in Neurodegenerative Disorders and Associated Cognitive Deficits

Azam

Haque

Jakaria

et al. 2020

Cells

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“…The NR4A2 (NURR1) transcription factor regulates the expression of important genes in the development and phenotype of dopaminergic neurons [1,2,50]. In addition, it participates in the modulation of metabolic, in ammatory, and cognitive processes [23,24,[51][52][53][54]. Alteration in the NR4A2 gene has been proposed as animal model of schizophrenia [18,19].…”

Section: Discussionmentioning

confidence: 99%

Working Memory Deficits in Schizophrenia Are Associated With the Rs34884856 Variant and Expression Levels of the NR4A2 Gene in a Sample Mexican Population: A Case Control Study

Ruiz-Sánchez

Jiménez-Genchi

Alcántara-Flores

et al. 2020

Preprint

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Background Cognitive functions represent useful endophenotypes to identify the association between genetic variants and schizophrenia. In this sense, the NR4A2 gene has been implicated in schizophrenia and cognition in different animal models and clinical trials. We hypothesized that the NR4A2 gene is associated with working memory performance in schizophrenia. This study aimed to analyze two variants and the expression levels of the NR4A2 gene with susceptibility to schizophrenia, as well as to evaluate whether possession of NR4A2 variants influence the possible correlation between gene expression and working memory performance in schizophrenia. Methods The current study included 187 schizophrenia patients and 227 controls genotyped for two of the most studied NR4A2 genetic variants in neurological and neuropsychiatric diseases. Genotyping was performed using High Resolution Melt and sequencing techniques. In addition, mRNA expression of NR4A2 was performed in peripheral mononuclear cells of 112 patients and 118 controls. A group of these participants, 54 patients and 87 controls, performed the working memory index of the WAIS III test. Results Both genotypic frequencies of the two variants and expression levels of the NR4A2 gene showed no significant difference when in patients versus controls. However, patients homozygous for the rs34884856 promoter variant showed a positive correlation between expression levels and auditory working memory. In these patients, a decrease of NR4A2 mRNA expression was related to working memory impairment. Conclusions Our finding suggested that changes in expression levels of the NR4A2 gene could be associated with working memory in schizophrenia depending on patients´ genotype in a sample from a Mexican population.

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“…Recently, several small molecules have been demonstrated to interact with Nur77 and modulate its transcriptional activity, including 1,1-bis(3 -indolyl)-1-(p-substitutedphenyl) methanes [213][214][215], the octaketide, cytosporone B [216], the PUFAs arachidonic acid (AA) and docosahexaenoic acid (DHA) [217] and prostaglandin A2 [218]. These synthetic and naturally occurring ligands have been demonstrated to induce Nur77-mediated protection against various processes including neuro-inflammation and neuronal cell death [219], cardiac remodeling [220], cancer cell proliferation [221] and inflammatory lung disease [222]. In addition to activation by ligands, Nur77 is under tonic inhibitory dopaminergic (DAergic) control mediated by D2 receptors in the striatum, the nucleus accumbens and the prefrontal cortex of the ventral midbrain region [194].…”

Section: Nerve Growth Factor Induced Clone B (Ngfi-b Nur77)mentioning

confidence: 99%

Nuclear Receptors as Regulators of Pituitary Corticotroph Pro-Opiomelanocortin Transcription

Zhang

Heaney

2020

Cells

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The hypothalamic–pituitary–adrenal (HPA) axis plays a critical role in adaptive stress responses and maintaining organism homeostasis. The pituitary corticotroph is the central player in the HPA axis and is regulated by a plethora of hormonal and stress related factors that synergistically interact to activate and temper pro-opiomelanocortin (POMC) transcription, to either increase or decrease adrenocorticotropic hormone (ACTH) production and secretion as needed. Nuclear receptors are a family of highly conserved transcription factors that can also be induced by various physiologic signals, and they mediate their responses via multiple targets to regulate metabolism and homeostasis. In this review, we summarize the modulatory roles of nuclear receptors on pituitary corticotroph cell POMC transcription, describe the unique and complex role these factors play in hypothalamic–pituitary–adrenal axis (HPA) regulation and discuss potential therapeutic targets in disease states.

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Molecular Insights into NR4A2(Nurr1): an Emerging Target for Neuroprotective Therapy Against Neuroinflammation and Neuronal Cell Death

Cited by 83 publications

References 154 publications

G-Protein-Coupled Receptors in CNS: A Potential Therapeutic Target for Intervention in Neurodegenerative Disorders and Associated Cognitive Deficits

G-Protein-Coupled Receptors in CNS: A Potential Therapeutic Target for Intervention in Neurodegenerative Disorders and Associated Cognitive Deficits

Working Memory Deficits in Schizophrenia Are Associated With the Rs34884856 Variant and Expression Levels of the NR4A2 Gene in a Sample Mexican Population: A Case Control Study

Nuclear Receptors as Regulators of Pituitary Corticotroph Pro-Opiomelanocortin Transcription

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