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Water-Soluble Arginyl–Diosgenin Analog Attenuates Hippocampal Neurogenesis Impairment Through Blocking Microglial Activation Underlying NF-κB and JNK MAPK Signaling in Adult Mice Challenged by LPS

  • Bangrong Cai
  • Kyung-Joo Seong
  • Sun-Woong Bae
  • Min Suk Kook
  • Changju Chun
  • Jin Ho Lee
  • Won-Seok Choi
  • Ji-Yeon JungEmail author
  • Won-Jae KimEmail author
Article
  • 11 Downloads

Abstract

Microglia-mediated neuroinflammatory responses are well known to inhibit neurogenesis in the dentate gyrus (DG) of the adult hippocampus, and growing evidence indicates that therapeutic intervention to suppress microglial activation could be an effective strategy for restoring the impaired neurogenesis and memory performance. In the present study, we investigated the effects of water-soluble arginyl–diosgenin analog (Arg-DG) on the adult hippocampal neurogenesis using a central LPS-induced inflammatory mice model, along with the fundamental mechanisms in vivo and in vitro using LPS-stimulated microglial BV2 cells. Arg-DG (0.6 mg/kg) attenuates LPS-impaired neurogenesis by ameliorating the proliferation and differentiation of neural stem cells (NSCs), and prolonging their survival. The impaired neurogenesis in the hippocampal DG triggered the cognitive function, and that treatment of Arg-DG led to the recovery of cognitive decline. Arg-DG also suppressed the production of LPS-induced pro-inflammatory cytokines in hippocampal DG by blocking microglial activation. In in vitro study, Arg-DG inhibited the production of nitric oxide (NO), nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2) expression, and prostaglandin D2 production (PGD2), as well as the pro-inflammatory cytokines, such as interleukin (IL)-6, IL-1β, and tumor necrosis factor alpha (TNF-α). The anti-inflammatory effect of Arg-DG was regulated by NF-κB and MAPK JNK signaling both in vivo, and in LPS-stimulated microglial BV2 cells. Taken together, these results suggest that Arg-DG might have the potential to treat various neurodegenerative disorders resulting from microglia-mediated neuroinflammation.

Keywords

Arginyl–diosgenin Adult neurogenesis LPS Microglia Neuroinflammation NF-κB JNK signaling 

Notes

Acknowledgments

This work was supported by the National Research Foundation of Korea (NRF) grant funded by the Korea government (MSIP) (2018R1D1A3B07051424, 2018R1A6A3A11040439, 2018R1D1A1B07049876) and by a grant from the Chonnam National University Hospital Research Institute of Clinical Medicine (CRI 12052-22).

Compliance with Ethical Standards

Conflict of Interest

The authors declare that they have no competing interests.

Supplementary material

12035_2019_1496_Fig11_ESM.png (736 kb)
Fig. S1

(A) Chemical structures of Arg-DG and (B) schematic of the experimental design. Mice were randomly divided into three groups (1, sham control; 2, Arg-DG treatment, LPS intracerebroventricular (I.C.V) injection; and LPS I.C.V. injection with Arg-DG co-treatment) and received 3 μg of LPS with I.C.V. injection. Arg-DG solution (0.6 mg/kg) dissolved in saline was intraperitoneally administrated (IP) three times at 8-h intervals after recovering from anesthesia. 5-Bromo-2-deoxyuridine (BrdU) was intraperitoneally injected at the indicated time points. Animals were sacrificed at the indicated date presented in the experimental schedule. (C) The proliferation of adult NSCs in the hippocampal DG was not affected by Arg-DG or PBS I.C.V. injection compared to sham control, as determined by the numbers of BrdU-positive cells using immunohistochemical analysis. (PNG 736 kb)

12035_2019_1496_MOESM1_ESM.tif (20 mb)
ESM 1 (TIF 20504 kb)

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Authors and Affiliations

  1. 1.School of PharmacyHenan University of Traditional Chinese MedicineZhengzhouChina
  2. 2.Dental Science Research Institute, Medical Research Center for Biomineralization Disorders, Department of Oral Physiology, School of DentistryChonnam National UniversityGwangjuRepublic of Korea
  3. 3.Department of Oral and Maxillofacial Surgery, School of DentistryChonnam National UniversityGwangjuSouth Korea
  4. 4.Research Institute of Drug Development, College of PharmacyChonnam National UniversityGwangjuRepublic of Korea
  5. 5.School of Biological Sciences and TechnologyChonnam National UniversityGwangjuRepublic of Korea

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