Abstract
Nuclear receptor related-1 (Nurr1) protein performs a crucial role in hippocampal neural stem cell (hNSC) development as well as cognitive functions. We previously demonstrated that the pharmacological stimulation of Nurr1 by amodiaquine (AQ) promotes spatial memory by enhancing adult hippocampal neurogenesis. However, the role of Nurr1 in the cell cycle regulation of the adult hippocampus has not been investigated. This study aimed to examine changes in the cell cycle-related molecules involved in adult hippocampal neurogenesis induced by Nurr1 pharmacological stimulation. Fluorescence-activated cell sorting (FACS) analysis showed that AQ improved the progression of cell cycle from G0/G1 to S phase in a dose-dependent manner, and MEK1 or PI3K inhibitors attenuated this progression. In addition, AQ treatment increased the expression of cell proliferation markers MCM5 and PCNA, and transcription factor E2F1. Furthermore, pharmacological stimulation of Nurr1 by AQ increased the expression levels of positive cell cycle regulators such as cyclin A and cyclin-dependent kinases (CDK) 2. In contrast, levels of CDK inhibitors p27KIP1 and p57KIP2 were reduced upon treatment with AQ. Similar to the in vitro results, RT-qPCR analysis of AQ-administered mice brains revealed an increase in the levels of markers of cell cycle progression, PCNA, MCM5, and Cdc25a. Finally, AQ administration resulted in decreased p27KIP1 and increased CDK2 levels in the dentate gyrus of the mouse hippocampus, as quantified immunohistochemically. Our results demonstrate that the pharmacological stimulation of Nurr1 in adult hNSCs by AQ promotes the cell cycle by modulating cell cycle-related molecules.
Highlights
The nuclear receptor-related 1 protein (Nurr1, NR4A2), a member of nuclear receptor subfamily 4A (NR4A), is expressed abundantly throughout the central nervous system during the developmental stage and adulthood [1,2,3,4,5]
We showed that Nuclear receptor related-1 (Nurr1) pharmacological stimulation by AQ promoted cell cycle progression in both hippocampal NSCs and the mouse hippocampus
We demonstrated that Nurr1 pharmacological stimulation by AQ promoted adult neurogenesis in both the mouse hippocampus and adult rat hippocampal neural stem cell (hNSC) [38]
Summary
The nuclear receptor-related 1 protein (Nurr, NR4A2), a member of nuclear receptor subfamily 4A (NR4A), is expressed abundantly throughout the central nervous system during the developmental stage and adulthood [1,2,3,4,5]. Nurr is involved in a variety of cognitive functions such as learning and memory [9,10,11,12,13,14]. Nurr haploinsufficiency is associated with cognitive and language impairment in humans [15,16]. The intracellular transcription factor Nurr has been suggested as a therapeutic target since it undergoes alterations and is involved in the pathology of neurodegenerative diseases including Parkinson’s disease (PD) and Alzheimer’s disease (AD) [17,18,19,20,21,22,23]. Amodiaquine (AQ) is reported as a pharmacological agonist showing direct interactions with the Nurr ligand-binding domain and upregulation of Nurr transcriptional activity [25]. In rodent models of PD and AD, AQ administration alleviates disease-related pathogenesis through Nurr activation [18,25]. AQ promotes midbrain dopaminergic neurogenesis, and restores impaired hippocampal neurogenesis in AD animal models [18,25]
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