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Glucocorticoids Suppress the Protective Effect of Cyclooxygenase-2-Related Signaling on Hippocampal Neurogenesis Under Acute Immune Stress

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Abstract

Stress and glucocorticoids suppress adult neurogenesis in the hippocampus. However, the molecular mechanisms underlying stress-induced impairment of adult neurogenesis are poorly understood. We previously suggested that cyclooxygenase (COX)-2 is a common mediator of stresses in the brain. Here, using a lipopolysaccharide (LPS)-induced acute infectious stress model, we evaluated the roles of COX-2 and its major downstream product prostaglandin E2 (PGE2) in adult neurogenesis and the influence of glucocorticoids on COX-2-related signaling. Treatment of rats with LPS significantly decreased neurogenesis in the dentate gyrus (DG) of the hippocampus, and this inhibitory effect of LPS on neurogenesis was reversed by the glucocorticoid receptor antagonist RU486. Moreover, RU486 significantly enhanced the increase in messenger RNA (mRNA) levels of COX-2 and microsomal prostaglandin E synthase (mPGES)-1 in the hippocampus following LPS stimulation. Administration of AH6809, a selective antagonist of the PGE2 EP2 receptor, as well as NS398, a COX-2 selective inhibitor, exacerbated the suppression of proliferation of neural progenitor cells (NPCs) in the DG. Gene expression of EP1, EP2, and EP3, but not EP4, receptors was also increased following LPS stimulation. Immunohistochemical studies indicated that NPCs expressed EP2 receptor, whereas the majority of cells expressing COX-2 and mPGES-1 were mature neurons in the DG. These results suggest that acute infectious stress upregulates COX-2-related signaling in neurons in the DG, which plays a protective role in neurogenesis through EP2 receptor at least partially. In addition, LPS-induced glucocorticoids suppress this COX-2-related signaling, resulting in decreased neurogenesis.

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Abbreviations

ANOVA:

Analysis of variance

BrdU:

Bromodeoxyuridine

COX-2:

Cyclooxygenase-2

DCX:

Doublecortin

DG:

Dentate gyrus

DMSO:

Dimethyl sulfoxide

EP:

Prostaglandin E2 receptors

GCL:

Granule cell layer

GFAP:

Glial fibrillary acidic protein

HPRT:

Hypoxanthine phosphoribosyltransferase

HSD:

Honestly significant difference

Iba-1:

Ionized calcium-binding adapter molecule 1

i.p.:

Intraperitoneally

LPS:

Lipopolysaccharide

mPGES-1:

Microsomal prostaglandin E synthase-1

NPCs:

Neural progenitor cells

NSCs:

Neural stem cells

PBS:

Phosphate-buffered saline

PGDS:

Prostaglandin D synthase

PGE2:

Prostaglandin E2

PGIS:

Prostaglandin I synthase

RT:

Reverse transcription

SGZ:

Subgranular zone

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Acknowledgments

This work was partly supported by JSPS KAKENHI (Grant Number 23228004 to MN) and a JSPS Postdoctoral Fellowship for Foreign Researchers (Grant Number 26.04906 to YM).

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Authors and Affiliations

  1. Department of Veterinary Physiology, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Tokyo, 113-8657, Japan

    Yanbo Ma, Takashi Matsuwaki, Keitaro Yamanouchi & Masugi Nishihara

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  1. Yanbo Ma
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Correspondence to Masugi Nishihara.

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Ma, Y., Matsuwaki, T., Yamanouchi, K. et al. Glucocorticoids Suppress the Protective Effect of Cyclooxygenase-2-Related Signaling on Hippocampal Neurogenesis Under Acute Immune Stress. Mol Neurobiol 54, 1953–1966 (2017). https://doi.org/10.1007/s12035-016-9766-9

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