Lipopolysaccharide-Induced Behavioral Alterations Are Alleviated by Sodium Phenylbutyrate via Attenuation of Oxidative Stress and Neuroinflammatory Cascade

Jangra, Ashok; Sriram, Chandra Shaker; Lahkar, Mangala

doi:10.1007/s10753-016-0376-5

Cited by 61 publications

(19 citation statements)

References 52 publications

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“…Furthermore, a recent report indicated that ER stress can activate NLRP3 inflammasome in macrophage stimulated by pathogen alone in the absence of NLRP3 inflammasome activators [43]. Additionally, increased levels of ER stress makers were observed in the brain after LPS ip injection and relief of ER stress decreased brain cytokine production including IL-1β [57]. Therefore, we investigated a potential role of ER stress in mediating LPS aloneinduced NLRP3-dependent mature IL-1β production in microglia.…”

Section: Er Stress Mediates Lps Alone-induced Nlrp3-dependent Il-1β Pmentioning

confidence: 94%

A novel role of NLRP3-generated IL-1β in the acute-chronic transition of peripheral lipopolysaccharide-elicited neuroinflammation: implications for sepsis-associated neurodegeneration

Zhao

Wang

Zhou

et al. 2020

J Neuroinflammation

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Background: Sepsis-associated acute brain inflammation, if unresolved, may cause chronic neuroinflammation and resultant neurodegenerative diseases. However, little is known how the transition from acute to chronic neuroinflammation, which is critical for the following progressive neurodegeneration, occurs in sepsis. The goal of this study was to investigate potential immune factors regulating the transition process using a widely used endotoxemia LPS mouse model. This model shows distinct acute and chronic phases of neuroinflammation and recapitulates many cardinal features of Parkinson's disease, thus, providing a unique opportunity for studying phase transition of neuroinflammation.Methods: C57BL/6 J, NLRP3 −/− , and IL-1R1 −/− mice were employed. Mild and severe endotoxemia were produced by LPS ip injection at 1 or 5 mg/kg. Neuroinflammation in vitro and in vivo was assessed with proinflammatory cytokine expression by qPCR or ELISA and microglial activation by immunohistochemical analysis. Neurodegeneration was measured by manual and stereological counts of nigral dopaminergic neurons and immunohistochemical analysis of protein nitrosylation and α-synuclein phosphorylation. Results: LPS-elicited initial increases in mouse brain mRNA levels of TNFα, IL-6, IL-1β, and MCP-1, and nigral microglial activation were not dose-related. By contrast, the delayed increase in brain mature IL-1β levels was dependent on LPS doses and protracted nigral microglial activation was only observed in high dose of LPS-treated mice. LPS-elicited increase in brain mature IL-1β but not IL-1α level was NLRP3-dependent. After high dose LPS treatment, deficiency of NLRP3 or IL-1R1 did not prevent the initiation of acute neuroinflammation but abolished chronic neuroinflammation. Genetic or pharmacological inhibition of the NLRP3-IL-1β axis repressed LPS-stimulated upregulation of chronic neuroinflammatory mediators including MHC-II, NOX2, and Mac1, and protected dopaminergic neurons. Ten months after LPS-elicited severe endotoxemia, nigral persisted microglial activation, elevated nitrosylated proteins and phosphorylated α-synuclein, and significant neuronal degeneration developed in wild-type mice but not in NLRP3 −/− or IL-1R1 −/− mice.

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Section: Er Stress Mediates Lps Alone-induced Nlrp3-dependent Il-1β Pmentioning

confidence: 94%

A novel role of NLRP3-generated IL-1β in the acute-chronic transition of peripheral lipopolysaccharide-elicited neuroinflammation: implications for sepsis-associated neurodegeneration

Zhao

Wang

Zhou

et al. 2020

J Neuroinflammation

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“…Each rat was placed at the center of maze with head facing towards the open arm and allowed to freely explore for 5 min. The total number of entries into the open arm, closed arm, and time spent in open arm during the test were recorded and evaluated [ 29 ].…”

Section: Methodsmentioning

confidence: 99%

Neuroprotective Effects of dl‐3‐n‐Butylphthalide against Doxorubicin‐Induced Neuroinflammation, Oxidative Stress, Endoplasmic Reticulum Stress, and Behavioral Changes

Liao

Xiang

Dang

et al. 2018

Oxidative Medicine and Cellular Longevity

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Doxorubicin (DOX) is a broad-spectrum antitumor drug while its use is limited due to its neurobiological side effects associated with depression. We investigated the neuroprotective efficacy of dl-3-n-butylphthalide (dl-NBP) against DOX-induced anxiety- and depression-like behaviors in rats. dl-NBP was given (30 mg/kg) daily by gavage over three weeks starting seven days before DOX administration. Elevated plus maze (EPM) test, forced swimming test (FST), and sucrose preference test (SPT) were performed to assess anxiety- and depression-like behaviors. Our study showed that the supplementation of dl-NBP significantly mitigated the behavioral changes induced by DOX. To further explore the mechanism of neuroprotection induced by dl-NBP, several biomarkers including oxidative stress markers, endoplasmic reticulum (ER) stress markers, and neuroinflammatory cytokines in the hippocampus were quantified. The results showed that dl-NBP treatment alleviated DOX-induced neural apoptosis. Meanwhile, DOX-induced oxidative stress and ER stress in the hippocampus were significantly ameliorated in dl-NBP pretreatment group. Our study found that dl-NBP alleviated the upregulation of malondialdehyde (MDA), nitric oxide (NO), CHOP, glucose-regulated protein 78 kD (GRP-78), and caspase-12 and increased the levels of reduced glutathione (GSH) and activities of catalase (CAT), glutathione reductase (GR), and glutathione peroxidase (GPx) in the hippocampus of rats exposed to DOX. Additionally, the gene expression of interleukin-6 (IL-6), interleukin-1β (IL-1β), and tumor necrosis factor-alpha (TNF-α) and protein levels of inducible nitric oxide synthase (iNOS) were significantly increased in DOX-treated group, whereas DOX-induced neuroinflammation was significantly attenuated in dl-NBP supplementation group. In conclusion, dl-NBP could alleviate DOX-induced anxiety- and depression-like behaviors via attenuating oxidative stress, ER stress, inflammatory reaction, and neural apoptosis, providing a basis as a therapeutic potential against DOX-induced neurotoxicity.

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“…Increasing evidence indicates that the neurotrophic hypothesis of neuropsychiatric disorders is based on the downregulation of brain-derived neurotrophic factor (BDNF) and the neuropeptide VGF (no acronym) expression in the brain [ 16 – 21 ]. In addition, previous studies have demonstrated that LPS-induced pro-inflammatory cytokine mediate the generation of oxidative parameters [ 9 , 22 ] and the impairment of BDNF [ 23 ] and VGF functions [ 7 ]. Intervening in the process of neuroinflammation along with oxidative stress may be beneficial for the therapy of neuropsychiatric disorders.…”

Section: Introductionmentioning

confidence: 99%

Lentivirus-mediated interleukin-1β (IL-1β) knock-down in the hippocampus alleviates lipopolysaccharide (LPS)-induced memory deficits and anxiety- and depression-like behaviors in mice

et al. 2017

J Neuroinflammation

181

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BackgroundRecent evidence has suggested that peripheral inflammatory responses induced by lipopolysaccharides (LPS) play an important role in neuropsychiatric dysfunction in rodents. Interleukin-1β (IL-1β), a pro-inflammatory cytokine, has been proposed to be a key mediator in a variety of behavioral dysfunction induced by LPS in mice. Thus, inhibition of IL-1β may have a therapeutic benefit in the treatment of neuropsychiatric disorders. However, the precise underlying mechanism of knock-down of IL-1β in repairing behavioral changes by LPS remains unclear.MethodsThe mice were treated with either IL-1β shRNA lentivirus or non-silencing shRNA control (NS shRNA) lentivirus by microinjection into the dentate gyrus (DG) regions of the hippocampus. After 7 days of recovery, LPS (1 mg/kg, i.p.) or saline was administered. The behavioral task for memory deficits was conducted in mice by the novel object recognition test (NORT), the anxiety-like behaviors were evaluated by the elevated zero maze (EZM), and the depression-like behaviors were examined by the sucrose preference test (SPT) and the forced swimming test (FST). Furthermore, the levels of malondialdehyde (MDA), superoxide dismutase (SOD), nuclear factor erythroid-derived 2-like 2 (Nrf2), heme oxygenase 1 (HO1), IL-1β, tumor necrosis factor (TNF-α), neuropeptide VGF (non-acronymic), and brain-derived neurotrophic factor (BDNF) were assayed.ResultsOur results demonstrated that IL-1β knock-down in the hippocampus significantly attenuated the memory deficits and anxiety- and depression-like behaviors induced by LPS in mice. In addition, IL-1β knock-down ameliorated the oxidative and neuroinflammatory responses and abolished the downregulation of VGF and BDNF induced by LPS.ConclusionsCollectively, our findings suggest that IL-1β is necessary for the oxidative and neuroinflammatory responses produced by LPS and offers a novel drug target in the IL-1β/oxidative/neuroinflammatory/neurotrophic pathway for treating neuropsychiatric disorders that are closely associated with neuroinflammation, oxidative stress, and the downregulation of VGF and BDNF.

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Lipopolysaccharide-Induced Behavioral Alterations Are Alleviated by Sodium Phenylbutyrate via Attenuation of Oxidative Stress and Neuroinflammatory Cascade

Cited by 61 publications

References 52 publications

A novel role of NLRP3-generated IL-1β in the acute-chronic transition of peripheral lipopolysaccharide-elicited neuroinflammation: implications for sepsis-associated neurodegeneration

A novel role of NLRP3-generated IL-1β in the acute-chronic transition of peripheral lipopolysaccharide-elicited neuroinflammation: implications for sepsis-associated neurodegeneration

Neuroprotective Effects of dl‐3‐n‐Butylphthalide against Doxorubicin‐Induced Neuroinflammation, Oxidative Stress, Endoplasmic Reticulum Stress, and Behavioral Changes

Lentivirus-mediated interleukin-1β (IL-1β) knock-down in the hippocampus alleviates lipopolysaccharide (LPS)-induced memory deficits and anxiety- and depression-like behaviors in mice

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