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.

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Alzheimer’s disease (AD), which is the most major cause of dementia, is a progressive neurodegenerative disease that affects cognitive functions. Even though the prevalence of AD is continuously increasing, few drugs including cholinesterase inhibitors and N-methyl D-aspartate-receptor antagonists were approved to treat AD. Because the clinical trials of AD drugs with single targets, such as β-amyloid and tau, have failed, the development of multi-target drugs that ameliorate many of the symptoms of AD is needed. Thus, recent studies have investigated the effects and underlying mechanisms of herbal formulae consisting of various herb combinations used to treat AD. This review discusses the results of clinical and nonclinical studies of the therapeutic efficacy in AD and underlying mechanisms of the herbal formulae of traditional Oriental medicines and bioactive compounds of medicinal plants.