Electroconvulsive seizures (ECS) do not prevent LPS-induced behavioral alterations and microglial activation

Buel, E. M. van; Bosker, Fokko J.; Drunen, J. van; Strijker, J.; Douwenga, Wanda; Klein, Hans; Eisel, Ulrich

doi:10.1186/s12974-015-0454-x

Cited by 14 publications

(8 citation statements)

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“…All of these observations suggest that targeting the neuroinflammatory system to develop new therapeutic strategies for the treatment of depression might provide a novel and valuable route for future research in this area. Microglial reactivity was found in the hippocampus of rodents following exposure to chronic unpredictable stress and LPS-induced depressive-like behavior [ 26 , 27 ], while suppressing LPS-induced microglia activation and pro-inflammatory cytokine production in the hippocampus could significantly attenuate the neuroinflammation and depressive-like behaviors [ 28 – 31 ]. In response to stressful conditions, microglial cells have the capacity to change their morphology from a surveillance phenotype to one of an enlarged soma and retracted processes [ 32 , 33 ], effects which, together with astrocytes, are usually associated with the production of pro-inflammatory cytokines [ 34 ].…”

Section: Discussionmentioning

confidence: 99%

Hippocampal CA1 βCaMKII mediates neuroinflammatory responses via COX-2/PGE2 signaling pathways in depression

Song

Fan

Wang

et al. 2018

J Neuroinflammation

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BackgroundNeuroinflammation has recently emerged as a critical risk factor in the pathophysiology of depression. However, the underlying molecular mechanisms and the development of novel therapeutic strategies as means to target these inflammatory pathways for use in the treatment of depression remain unresolved. In the present study, we aimed to investigate the molecular events of neuroinflammation as related to its induction of depression-like behaviors.MethodsChronic unpredictable mild stress (CUMS) or lipopolysaccharide (LPS) was used to induce depression-like behaviors in rats. The inflammatory factors and related proteins were verified by RT-PCR, immunoblotting, and immunofluorescence assay. In vivo intracerebral injection of adenovirus-associated virus (AAV) in rats was used to overexpress or block the function of the β form of the calcium/calmodulin-dependent protein kinase type II (βCaMKII). In vivo intracerebroventricular injection of SB203580 was used to block p38 mitogen-activated protein kinase (MAPK). Finally, the prostaglandin E2 (PGE2) concentration was verified by using enzyme-linked assay kit.ResultsThe expression of cyclo-oxygenase (COX)-2, which is responsible for production of the pro-inflammatory factor PGE2 and thus glial activation, was increased in the CA1 hippocampus in a rat model of depression. Further, the βCaMKII in CA1 was significantly upregulated in depressed rats, while antidepressant treatment downregulated this kinase. Overexpression of βCaMKII via infusion of a constructed AAV-βCaMKII into the CA1 region resulted in phosphorylation of the p38 MAPK and the activating transcription factor 2 (ATF2). These effects were accompanied by an enhanced activity of the COX-2/PGE2 pathway and effectively induced core symptoms of depression. Conversely, knockdown of βCaMKII within the CA1 region reversed these inflammation-related biochemical parameters and significantly rescued depression symptoms.ConclusionThese results demonstrate that βCaMKII can act as a critical regulator in depression via activating neuroinflammatory pathways within the CA1 region. Moreover, this study provides new perspectives on molecular targets and drug therapies for future investigation in the treatment of depression.Electronic supplementary materialThe online version of this article (10.1186/s12974-018-1377-0) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 99%

Hippocampal CA1 βCaMKII mediates neuroinflammatory responses via COX-2/PGE2 signaling pathways in depression

Song

Fan

Wang

et al. 2018

J Neuroinflammation

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“…The first objective of our present study was to explore the involvement of IL-1β in the behavioral dysfunction induced by a peripheral immune challenge in mice. The mechanisms of central or peripheral treatment with LPS on behavioral dysfunctions in rodents trigger an increase in the expression of pro-inflammatory cytokines [ 7 , 34 , 35 ]. Herein, we found that peripheral administration of LPS causes the elevation of IL-1β and TNF-α levels in the hippocampus of mice, which may have contributed to the behavioral alterations.…”

Section: Discussionmentioning

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

190

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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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“…To further demonstrate the pathogenesis of NHE1-regulated depression, we employed LPS to induce depressive-like symptoms in mice 18,19 because LPS could activate NHE1, which is related to the activation of ROCK2 and excessive aggregation of Ca 2+ in the cytoplasm. Furthermore, LPS treatment triggers inflammatory responses, leading to neuronal apoptosis, which is also a well-established animal model of depression.…”

Section: Resultsmentioning

confidence: 99%

“…In endothelial cells, LPS stimulated NHE1 activation and increased Ca 2+ concentration, which led to endothelial cell apoptosis 27 . LPS i.c.v., as a well-established animal model of depression, also activates NHE1, triggering inflammatory responses that lead to neuronal apoptosis 18 . By applying an inhibitor of NHE1, Ami, the depressive-like behaviours were significantly attenuated in the LPS-induced animal model of depression.…”

Section: Discussionmentioning

confidence: 99%

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Suppressing the Na+/H+ exchanger 1: a new sight to treat depression

Deng

et al. 2019

Cell Death Dis

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Na + /H + exchanger 1 (NHE1), an important regulator of intracellular pH (pHi) and extracellular pH (pHe), plays a crucial role in various physiological and pathological processes. However, the role of NHE1 in depression has not yet been reported. This study was designed to investigate the role of NHE1 in the animal model of depression and explore the underlying mechanisms. Our results showed that inhibition of rho-associated kinase 2 (ROCK2) by fasudil (Fas) or baicalin (BA) significantly alleviated chronic unpredictable mild stress (CUMS) paradigm-induced depression-related behaviours in mice, as shown by decreased sucrose consumption in sucrose preference test (SPT), reduced locomotor activity in the open field test (OFT), and increased immobility time in the tail suspension test (TST) and forced swimming test (FST). Furthermore, ROCK2 inhibition inhibited the activation of NHE1, calpain1, and reduced neuronal apoptosis in the CUMS animal model of depression. Next, we used the lipopolysaccharide (LPS)-challenged animal model of depression to induce NHE1 activation. Our results revealed that mice subjected to 1 μl LPS (10 mg/ml) injection intracerebroventricularly (i.c.v.) showed depressive-like behaviours and NHE1 activation. Amiloride (Ami), an NHE1 inhibitor, significantly reversed the decrease in sucrose consumption and reduction in immobility time in the TST and FST induced by LPS challenge. Furthermore, Ami decreased the expression of ROCK2, NHE1, calpain1, and caspase-3 and increased the Bcl-1/Bax ratio in the hippocampus of LPS-challenged mice. Ami treatment also led to antidepressive effects in the CUMS-induced animal model of depression. Thus ROCK2 inhibition could be proposed as a neuroprotective strategy against neuronal apoptosis, and NHE1 might be a potential therapeutic target in depression.

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Electroconvulsive seizures (ECS) do not prevent LPS-induced behavioral alterations and microglial activation

Cited by 14 publications

References 46 publications

Hippocampal CA1 βCaMKII mediates neuroinflammatory responses via COX-2/PGE2 signaling pathways in depression

Hippocampal CA1 βCaMKII mediates neuroinflammatory responses via COX-2/PGE2 signaling pathways in depression

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

Suppressing the Na+/H+ exchanger 1: a new sight to treat depression

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