title: 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.
authors: Department of Nursing, College of Nursing, Jeju National University, Jeju-si 63243, Republic of Korea.
authors: Jin-Il
authors: JI
authors: Kim
authors: Department of Biochemistry, College of Medicine, Konyang University, Daejeon 35365, Republic of Korea.
authors: Seong Gak
authors: SG
authors: Jeon
authors: Department of Biochemistry, College of Medicine, Konyang University, Daejeon 35365, Republic of Korea.
authors: Kyoung Ah
authors: KA
authors: Kim
authors: Department of Pathology, College of Medicine, Kyung Hee University, Seoul 02447, Republic of Korea.
authors: Yong Jun
authors: YJ
authors: Kim
authors: Department of Biochemistry, College of Medicine, Konyang University, Daejeon 35365, Republic of Korea.
authors: Eun Ji
authors: EJ
authors: Song
authors: Department of Core Research Laboratory, Clinical Research Institute, Kyung Hee University Hospital at Gangdong, Seoul 05278, Republic of Korea.
authors: Junghyun
authors: J
authors: Choi
authors: Department of Endocrinology and Metabolism, Kyung Hee University School of Medicine, Seoul 02447, Republic of Korea.
authors: Kyu Jeung
authors: KJ
authors: Ahn
authors: Department of Cardiology, Kyung Hee University School of Medicine, Seoul 02447, Republic of Korea.
authors: Chong-Jin
authors: CJ
authors: Kim
authors: Department of Endocrinology and Metabolism, Kyung Hee University School of Medicine, Seoul 02447, Republic of Korea.
authors: Ho Yeon
authors: HY
authors: Chung
authors: Department of Biochemistry, College of Medicine, Konyang University, Daejeon 35365, Republic of Korea. Electronic address: hominmoon@konyang.ac.kr.
authors: Minho
authors: M
authors: Moon
authors: Department of Core Research Laboratory, Clinical Research Institute, Kyung Hee University Hospital at Gangdong, Seoul 05278, Republic of Korea. Electronic address: hjchung@khu.ac.kr.
authors: Hyunju
authors: H
authors: Chung
mesh_terms: D000655:Amodiaquine / Q000494:pharmacology*; D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D006624:Hippocampus / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology*; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D055495:Neurogenesis / Q000187:drug effects* / Q000502:physiology; D057126:Nuclear Receptor Subfamily 4, Group A, Member 2 / Q000819:agonists* / Q000378:metabolism; D051381:Rats
chemical_list: C539882:NR4A2 protein, human; C539883:Nr4a2 protein, mouse; C539884:Nr4a2 protein, rat; D057126:Nuclear Receptor Subfamily 4, Group A, Member 2; D000655:Amodiaquine