Chronic dexamethasone treatment results in hippocampal neurons injury due to activate NLRP1 inflammasome in vitro

doi:10.1016/j.intimp.2017.05.039

International Immunopharmacology

Volume 49, August 2017, Pages 222-230

https://doi.org/10.1016/j.intimp.2017.05.039 Get rights and content

Highlights

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Chronic GCs exposure promotes hippocampal neurons damage.
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Chronic GCs exposure decreases GR expression in hippocampal neurons.
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Chronic GCs exposure activates NLRP1 inflammasome in hippocampal neurons.
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RU486 attenuates chronic GCs induced hippocampal neurons.

Abstract

Neuroinflammation mediated by NLRP-1 inflammasome plays an important role in the pathogenesis of neurodegeneration diseases such as Alzheimer's disease (AD). Chronic glucocorticoids (GCs) exposure has deleterious effect on the structure and function of neurons and was found to be correlated with development and progression of AD. We hypothesize that chronic glucocorticoids may down-regulate the expression of glucocorticoids receptor (GR) and activate NLRP-1 inflammasome in hippocampal neurons, which may promote neuroinflammation and induce neuronal injury. The present results showed that chronic DEX exposure significantly increased LDH release and apoptosis, decreased MAP2 and GR expression in hippocampal neurons. DEX (5 μΜ) exposure for 3 d significantly increased the expression of NLRP-1, ASC, caspase-1 and IL-1β in the hippocampal neurons and the release of IL-1β and IL-18 in the supernatants. Moreover, DEX (1, 5 μΜ) treatment for 3 d significantly increased the expression of NF-κB in hippocampal neurons. The GR antagonist, mifepristone (RU486), had protective effects on chronic DEX induced hippocampal neurons injury and NLRP1 inflammasome activation. The results suggest that chronic GCs exposure can decrease GR expression and increase neuroinflammation via NLRP1 inflammasome and promote hippocampal neurons degeneration, which may play an important role in the progression and development of AD.

Graphical abstract

Introduction

Glucocorticoids (GCs) hormones are principal stress mediators released from the adrenal gland in response to stressful events. Accumulating data implicated that chronic stress or GCs exposure produced abnormal behaviors in experimental animals and increased risk of psychiatric disorders in humans, such as Alzheimer's disease (AD) [1], [2], [3]. It has been reported that stress-level GCs could reduce hippocampal dendritic complexity [4], [5], and could promote hippocampal cell death [6]. Clinical assays indicated that plasma level of GCs was correlated with the rate of dementia progression in patients with AD [5]. These studies suggest that chronic exposure to stress-level GCs may result in alterations of neuronal architecture related to psychiatric disorders, but the precise molecular and cellular mechanisms of these alterations have not been fully elucidated.

It is well known that neuroinflammation plays an important role in the pathogenesis of neurodegeneration diseases such as AD. It is both a reaction to the disease process and a contributor to the neuronal injury [7], [8]. Recent study provided further evidence that inflammation involves in the pathogenesis of AD [9]. GCs have long been used as anti-inflammatory and immunosuppressive agents [10], and DEX is prescribed widely for the treatment of chronic inflammation, autoimmunity, and the prevention of transplant rejection [11]. However, not all actions of GCs are anti-inflammatory and immunosuppressive. Frank et al. reported that GCs have been shown to have a priming effect and can augment the immune response to LPS [12]. GCs could enhance the TNF-α-mediated increase of Toll-like receptor [13]. However, it is still unclear whether chronic GCs exposure could enhance neuroinflammation in hippocampal neurons and contribute to neuronal injury.

The inflammasome is a multiprotein complex that is responsible for the formation of proinflammatory molecules. Growing data show that neuroinflammation mediated by the inflammasome plays an important role in many neurological diseases [14]. The nucleotide-binding oligomerization domain (NOD)-like receptor protein 1 (NLRP-1) inflammasome mainly presents in neurons and glial cells and plays an important role in neurodegeneration diseases [15]. The hippocampus is a key brain region important for memory and contains a high density of glucocorticoids receptor (GR), which attribute to regulate the activities of the proinflammatory molecules by gene transcription [16], [17]. Our previous studies showed that chronic stress and chronic dexamethasone (DEX, 5 mg/kg) exposure 21 d could induce learning and memory impairment and hippocampal neurons damage [18], [19]. Recent studies have identified stress-induced proinflammatory cytokine IL-1β as a critical mediator of the neurodegeneration and the depression-like behavior caused by stress [20], [21]. Whether chronic GCs exposure can induce neuronal damage by activating NLRP-1 inflammasome in hippocampal neurons remains unclear. We hypothesize that chronic glucocorticoids may down-regulate the expression of GR and activate hippocampal neuronal NLRP1 inflammasome, which promote neuroinflammation and induce neuronal injury. To clarify our hypothesis, we investigated the effects of DEX (5 μM) treatment for 1 d, 3 d and 5 d and DEX (0.1, 1, 5 μM) treatment for 3 d on hippocampal neurons injury and NLRP-1 inflammasome activation in vitro. The study had the potential to contribute to a more complete understanding of the mechanism by which GCs may involve in neurodegeneration and progression of Alzheimer's disease.

Section snippets

Primary hippocampal neurons cultures and experimental treatment

Primary hippocampal neurons were prepared from hippocampus of postnatal (within 24 h) Sprague Dawley rats and cultured in Neurobasal medium and B-27 supplement (Invitrogen) as described previously [22], [23]. Cells were plated onto poly-l-lysine (10 μg/ml)-coated 96-well tissue culture plates (5 × 10⁴ cells/well) or 6-well tissue culture plates (1 × 10⁷ cells/well) or glass coverslips in 24-well tissue culture plates (1.5 × 10⁵ cells/well), then grown in Neurobasal medium containing 2% B-27 supplement.

Effects of chronic DEX exposure on neuronal damage and apoptosis

We hypothesized that chronic GCs exposure may promote neuroinflammation and induce hippocampal neurons injury, thus we firstly examined the effects of chronic DEX treatment on hippocampal neurons damage via LDH release assay and Hoechst 33258 staining. The LDH release results showed that DEX (1, 5 μM) treatment for 3 d significantly induced neuronal damage and increased LDH release (Fig. 1A, P < 0.01). We further measured the LDH release induced by DEX 5 μM treatment for 1 d, 3 d and 5 d. Our results

Discussion

In the current study, we demonstrated that chronic stress levels of DEX treatment significantly activate the NLRP-1 inflammasome in hippocampal neurons, which may be accountable for GCs induced hippocampal neuronal injury. Meanwhile, the GCs receptor antagonist, RU486, has an inhibitory and protective effect on chronic DEX induced NLRP-1 inflammasome activation and neuronal damage. GCs are the primary hormones released from the adrenal gland in response to stressful events. Growing studies have

Conclusion

Overall, this study demonstrates that chronic GCs exposure accelerates NLRP-1 inflammasome activation and induces neurodegeneration in hippocampal neurons. Our findings provide support for the hypothesis that chronic GCs exposure may down-regulate GR expression and induce neuroinflammation via NLRP1 inflammasome activation and promote hippocampal neurons degeneration which plays an important role in the development of AD.

Conflict of interest

The authors declare that they have no conflict of interest.

Acknowledgments

This study was financially supported by grants from the National Natural Science Foundation of China (81371329 and 81671384) and the Natural Science Foundation of Anhui Province Education Department (KJ2015A298, KJ2016A357). And thank Bao Li and Li Gui (Synthetic Laboratory of Basic Medicine College, Anhui Medical University) for their excellent technical assistance.

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¹: Biqiong Zhang, Yaodong Zhang and Tanzhen Xu contributed equally to the production of this publication.

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Chronic dexamethasone treatment results in hippocampal neurons injury due to activate NLRP1 inflammasome in vitro

Highlights

Abstract

Graphical abstract

Introduction

Section snippets

Primary hippocampal neurons cultures and experimental treatment

Effects of chronic DEX exposure on neuronal damage and apoptosis

Discussion

Conclusion

Conflict of interest

Acknowledgments

Metabolism

Exp. Neurol.

Mol. Cell. Endocrinol.

Brain Behav. Immun.

Eur. J. Pharmacol.

Pharmacol. Biochem. Behav.

Pharmacol. Biochem. Behav.

Neurochem. Int.

Brain Behav. Immun.

Int. J. Dev. Neurosci.

Brain Res.

Biomed. Pharmacother.

Trends Immunol.

Biochem. Pharmacol.

Proneness to psychological distress and risk of Alzheimer disease in a biracial community

Neurology

Stress and disease: is being female a predisposing factor?

J. Neurosci.

Chronic glucocorticoids increase hippocampal vulnerability to neurotoxicity under conditions that produce CA3 dendritic retraction but fail to impair spatial recognition memory

J. Neurosci.

Plasma cortisol and progression of dementia in subjects with Alzheimer-type dementia

Am. J. Psychiatry

Inflammation in Alzheimer's disease: relevance to pathogenesis and therapy

Alzheimers Res. Ther.

Inflammatory components in human Alzheimer's disease and after active amyloid-beta42 immunization

Brain

Suppression of Alzheimer-associated inflammation by microglial prostaglandin-E2 EP4 receptor signaling

J. Neurosci.

Anti-inflammatory action of glucocorticoids—new mechanisms for old drugs

N. Engl. J. Med.

Glucocorticoids and tumor necrosis factor alpha cooperatively regulate toll-like receptor 2 gene expression

Mol. Cell. Biol.

The inflammasome sensor, NLRP3, regulates CNS inflammation and demyelination via caspase-1 and interleukin-18

J. Neurosci.