The pharmacological stimulation of Nurr1 improves cognitive functions via enhancement of adult hippocampal neurogenesis

Abstract

The nuclear receptor related-1 (Nurr1) protein plays an important role in both the development of neural precursor cells (NPCs) and cognitive functions. Despite its relevance, the effects of Nurr1 on adult hippocampal neurogenesis have not been thoroughly investigated. Here we used RT-PCR, western blot, and immunocytochemistry to show that adult hippocampal NPCs abundantly express Nurr1. We then examined the effect of Nurr1 activation on adult hippocampal NPCs using amodiaquine (AQ), an anti-malarial drug that was recently discovered to be a Nurr1 agonist. Cell proliferation assay showed that AQ significantly increased cell proliferation. AQ-treated NPCs showed increased levels of phosphorylation of Akt and ERK1/2 whereas AQ-treated Nurr1 siRNA-transfected NPCs showed no changes in those levels. Further immunocytochemical and immunohistochemical analyses confirmed the stimulating effect of Nurr1 agonist on the proliferation and differentiation of adult hippocampal NPCs both in vivo and in vitro. In addition to its effects on proliferation and differentiation of NPCs, AQ-treated mice showed a significant enhancement of both short- and long-term memory in the Y-maze and the novel object recognition test. These data suggest that activation of Nurr1 may enhance cognitive functions by increasing adult hippocampal neurogenesis and also indicate that Nurr1 may be used as a therapeutic target for the treatment of memory disorders and cognitive impairment observed in neurodegenerative diseases.

Parkinson's disease, aging and adult neurogenesis: Wnt/β‐catenin signalling as the key to unlock the mystery of endogenous brain repair

“…Tfam has been shown to play a central role in the mtDNA stress‐mediated inflammatory response and recent evidence indicates that decreased mtDNA copy number is associated with several aging‐related pathologies (Kang et al, ). Of special mention, besides its crucial role for the development, maintenance and protection of midbrain DAergic neurons, the relevance of the transcription factor Nurr1 for adult hippocampal neurogenesis in PD has been recently highlighthed, and several lines of evidence indicate that pharmacological stimulation of Nurr1 can improve behavioral deficits via an increase in hippocampal neurogenesis (Kim et al, ; Kim et al, and section 6.4.1).…”

“…A number of studies documented the importance of Nurr1 and WβC/Nurr1 signalling pathways in promoting neurogenesis from DAergic precursors (reviewed in Arenas, ; Toledo et al, ; Section 2 and section, sectionprevious sections). Several studies have reported the contribution of Nurr1 in the modulation of cognitive functions (see Kim et al, ; Kim et al, , and refs therein). Specifically, the pharmacological stimulation of Nurr1 was shown to improve cognitive functions via the enhancement of hippocampal neurogenesis (Kim et al, , ), very likely via up‐regulation of WβC‐signalling.…”

“…Several studies have reported the contribution of Nurr1 in the modulation of cognitive functions (see Kim et al, ; Kim et al, , and refs therein). Specifically, the pharmacological stimulation of Nurr1 was shown to improve cognitive functions via the enhancement of hippocampal neurogenesis (Kim et al, , ), very likely via up‐regulation of WβC‐signalling. Hence, Kim et al () identified two antimalarial drugs, amodiaquine (AQ) and chloroquine that stimulated the transcriptional function of Nurr1.…”

“…In the inset, a schematic drawing of the four SVZ-cell types: 1. slowly dividing SVZ astrocytes (type B cells), 2. rapidly dividing transitamplifying cells (type C cells, TAPs), 3. migrating neuroblasts (type A cells), and 4. ependymal cells (type E cells) (Doetsch et al, 1997(Doetsch et al, , 1999 several aging-related pathologies (Kang et al, 2018). Of special mention, besides its crucial role for the development, maintenance and protection of midbrain DAergic neurons, the relevance of the transcription factor Nurr1 for adult hippocampal neurogenesis in PD has been recently highlighthed, and several lines of evidence indicate that pharmacological stimulation of Nurr1 can improve behavioral deficits via an increase in hippocampal neurogenesis (Kim et al, 2015;Kim et al, 2016 and section 6.4.1).…”

“…Enhanced olfactory memory in mice exposed to extremely low frequency electromagnetic fields via WβC-AC-induced modulation of SVZ-neurogenesis Mastrodonato et al (2018) Transcription factors Nurr1 agonists; amodiaquine (AQ), pharmacological stimulation AQ stimulates Nurr1's transcriptional function, enhancing adult hippocampal neurogenesis; WβC-AC involvement to be elucidated Kim et al (2016) Pharmacological stimulation of Nurr1 induces neuroprotection and anti-inflammatory effects in the 6-OHDA PD-model; WβC-AC involvement to be elucidated Smith et al (2015) Nanoparticles ( Note: 6-OHDA, 6-hydroxydopamine; BDNF, brain-derived neurotrophic factor; DA, dopamine; DCX, doublecortin; GSK-3β, glycogen synthase kinase 3β; Hmox1, heme oxygenase 1; L-NAME, N ω -Nitro-L-arginine methyl ester hydrochloride; MPP + , 1-methyl-4-phenylpyridinium; MPTP, 1-methyl-4phenyl-1,2,3,6-tetrahydropyridine; NO-NSAID, nitric oxide-releasing non-steroidal anti-inflammatory drugs; Nrf2, nuclear factor erythroid 2-related factor 2; NSC, neural stem/progenitor cell; Nurr1, nuclear receptor related 1 protein; PI3K, phosphoinositide 3-kinase; SNpc, substantia nigra pars compacta; SVZ, sub-ventricular zone; TNF-α, tumor necrosis factor alpha; VM, ventral midbrain; WβC-AC, Wnt/β-catenin signalling activation.…”