Protein arginine methyltransferase-1 deficiency restrains depression-like behavior of mice by inhibiting inflammation and oxidative stress via Nrf-2

doi:10.1016/j.bbrc.2019.08.032

Biochemical and Biophysical Research Communications

Volume 518, Issue 3, 20 October 2019, Pages 430-437

https://doi.org/10.1016/j.bbrc.2019.08.032 Get rights and content

Highlights

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Protein arginine methyltransferase-1 (PRMT1) deletion alleviates brain injury of LPS-induced mice.
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Knockout of PRMT1 attenuates LPS-induced inflammation and oxidative stress in hippocampus of mice.
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PRMT1 ablation ameliorates inflammation and oxidative stress in LPS-exposed astrocytes via Nrf-2.

Abstract

Current evidence indicates that depression is accompanied by the activation of inflammatory response and oxidative stress. Protein arginine methyltransferase 1 (PRMT1) is a histone methyltransferase that methylates Arg3 on histone H4, playing crucial role in regulating various pathological processes. In the study, we attempted to explore the effects of PRMT1 on animal model with depression through a single administration of lipopolysaccharide (LPS). Our results indicated that PRMT1 knockout (PRMT1^−/−) improved LPS-induced anxiety- and depressive-like behavior, along with up-regulated expression levels of brain-derived neurotrophic factor (BDNF) and PSD-95. Furthermore, PRMT1 deficiency significantly improved LPS-induced changes in dendritic spine density in the areas of prefrontal cortex (PFC), CA3 and dentate gyrus (DG), and nucleus accumbens (NAc). In addition, PRMT1 deletion ameliorated the neuroinflammatory responses, as evidenced by the reduced expression of interleukin 1β (IL-1β) and tumor necrosis factor (TNF)-α, which might be through repressing nuclear factor-κB (NF-κB) signaling. Moreover, oxidative stress induced by LPS was alleviated by PRMT1 knockout in hippocampus of mice at least partly via promoting Nrf-2 expressions. The anti-depressant effects of PRMT1 inhibition were verified in LPS-incubated astrocytes. Importantly, we found that PRMT1 knockout-alleviated inflammation and oxidative stress triggered by LPS were significantly recovered by the suppression of Nrf-2. Therefore, Nrf-2 was markedly involved in PRMT1-regulated depression-like behavior. Taken together, the results indicated that PRMT1 might be an important therapeutic target for developing effective treatment to prevent depressive-like behavior.

Introduction

Depression is one of the most common psychiatric disorders worldwide [1]. Despite the precise molecular mechanism underlying the pathophysiology of depression is unclear, multiple lines of evidence illustrate that inflammatory response and oxidative stress play a critical role in the pathophysiology of depression [2,3]. Also, a meta-analysis indicates higher blood levels of pro-inflammatory cytokines in drug-free depressed patients when compared to healthy controls [4,5]. Presently, peripheral administration of the bacterial endotoxin, LPS, triggers depression-like behavior in mice after the induction of inflammation, as well as oxidative stress [6]. Therefore, finding significant target associated with inflammation and oxidative stress might be effective for developing therapeutic strategy against depressive symptoms.

Protein arginine methyltransferase-1 (PRMT1), methylating both histones and key cellular proteins, has been served as a crucial modulator of various cellular processes, such as signal transduction, protein and protein interaction, as well as transcriptional modulation [7,8]. For instance, PRMT1 played an essential role in gene activation and metamorphosis triggered by ligand activated thyroid hormone receptor [9]. In addition, PRMT1 expression participates in fibroblast proliferation and chronic airway inflammation in Ag-induced pulmonary inflammation through the regulation of remodeling associated cytokines [10]. In vitro studies also suggested that angiotensin-II markedly induced PRMT1 expression and endothelial cell activation, thus producing reactive oxygen species (ROS) [11]. Thus, PRMT1 is involved in the meditation of inflammatory response and ROS generation. However, its influences on anxiety- and depression-like behaviors have not been investigated and reported.

The purpose of the study is to explore if PRMT1 could affect LPS-induced animal model with depression. The results suggested that PRMT1 deletion significantly improved anxiety- and depression-like behaviors induced by LPS in mice. Inflammatory response and oxidative stress induced by LPS were obviously ameliorated by the knockout of PRMT1 in hippocampus of mice. Notably, the in vitro experiments using LPS-treated astrocytes demonstrated that PRMT1-meditated inflammatory and oxidative damage was largely dependent on Nrf-2. Together, our study elucidated that PRMT1 could be served as a therapeutic candidate to develop effective treatment for alleviating depression.

Section snippets

Animals and treatments

Wild type C57BL/6 mice (adult male, PRMT1^+/+) weighing 22–25 g were obtained from the Vital River Laboratories (Beijing, China). PRMT1 knockout (PRMT1^−/−) mice with C57BL/6 background were constructed and purchased from Model Animal Research Center of Nanjing University (Nanjing, China). All mice were housed in a 12-h dark/light cycle, temperature (20 ± 2 °C) and humidity controlled environment with free access to water and food. 0.5 mg/kg of LPS (L-4130, serotype 0111:B4, Sigma-Aldrich, USA)

The influence of PRMT1 on anxiety- and depression-like behaviors induced by LPS in mice

In the regard, the effects of PRMT1 on anxiety- and depression-like behaviors induced by LPS were investigated. In the locomotion test, no significant differences were observed (Fig. 1A). TST and FST results suggested that PRMT1 knockout significantly attenuated the increased immobility time in mice after LPS treatment (Fig. 1B and C). Moreover, PRMT1 deletion produced a complementary up-regulation in swimming time compared to LPS/PRMT1^+/+ group (Fig. 1D). In the sucrose preference test,

Discussion

Accumulating evidence suggests that inflammation, increased cytokine levels and oxidative stress are related to anxiety- and depression-like symptoms and neuropsychological disturbances in humans [[3], [4], [5]]. In rodent animals, increasing studies have proved that depressive-like behaviors could be induced by cytokines or cytokine inducers, including LPS administration or chronic mild stress [6]. As reported, targeting the neuroinflammatory disturbances has been acknowledged as a potential

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Protein arginine methyltransferase-1 deficiency restrains depression-like behavior of mice by inhibiting inflammation and oxidative stress via Nrf-2

Highlights

Abstract

Introduction

Section snippets

Animals and treatments

The influence of PRMT1 on anxiety- and depression-like behaviors induced by LPS in mice

Discussion

Prog. Neuro Psychopharmacol. Biol. Psychiatry

Biol. Psychiatry

Brain Behav. Immun.

Mol. Cell

J. Neuroinflammation

Neuropharmacology

Int. Immunopharmacol.

Behav. Brain Res.

Eur. J. Pharmacol.

Pharmacol. Biochem. Behav.

Behav. Brain Res.

Clin. Interv. Aging

Biochem. Pharmacol.

Food Chem. Toxicol.

Common psychiatric disorders share the same genetic origin: a multivariate sibling study of the Swedish population

Mol. Psychiatry

Influence of anti-depression therapy on inflammatory cytokines and quality of life in patients with acute coronary syndrome complicating depression

Int. J. Lab. Med.

Effects of doxycycline on depressive-like behavior in mice after lipopolysaccharide (LPS) administration

J. Psychiatr. Res.

Methyltransferase PRMT1 Is a binding partner of HBx and a negative regulator of hepatitis B virus transcription

J. Virol.

Methylation of RUNX1 by PRMT1 abrogates SIN3A binding and potentiates its transcriptional activity

Genes Dev.

PRMT1 upregulated by epithelial proinflammatory cytokines participates in COX2 expression in fibroblasts and chronic antigen-induced pulmonary inflammation

J. Immunol.