Lipopolysaccharide-induced sepsis-like state compromises post-ischemic neurological recovery, brain tissue survival and remodeling via mechanisms involving microvascular thrombosis and brain T cell infiltration

Sardari, Maryam; Škuljec, Jelena; Yin, Dongpei; Zec, Kristina; Carvalho, Tayana Silva de; Albers, Dan; Wang, Chen; Pul, Refik; Popa‐Wagner, Aurel; Doeppner, Thorsten R.; Kleinschnitz, Christoph; Dzyubenko, Egor; Hermann, Dirk M.

doi:10.1016/j.bbi.2020.10.015

Cited by 18 publications

(20 citation statements)

References 41 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In agreement with our previous study on C57BL/6 mice using a very similar model of LPS-induced sepsis-like state ( Sardari et al, 2020b ), we here report in NMRI mice that post-ischemic delivery of LPS (2 or 4 mg/kg) dose-dependently induced a sepsis-like state characterized by rectal hypothermia. Very similar to the previous study ( Sardari et al, 2020b ), LPS-induced sepsis increased neurological deficits evaluated by Clark score, cylinder, and open-field tests, increased infarct volume evaluated by TTC stainings and decreased neuronal survival evaluated by Nissl stainings. Interestingly, additional treatment with the non-competitive NMDA receptor antagonist ketamine (10 mg/kg) significantly attenuated the sepsis-associated hypothermia, reversed the LPS-induced neurological deficits, reduced infarct volume and increased neuronal survival.…”

Section: Discussionsupporting

confidence: 93%

“…The Clark score consists of two subscores capturing general and focal neurological deficits ( Clark et al, 2016 ; Sardari et al, 2020b ). General and focal deficits were evaluated at baseline, at 3, 6, and 24 hpi before LPS-induced sepsis, and at 27, 30, 48, 72, and 96 hpi (that is, at 3, 6, 24, and 72 h) after LPS-induced sepsis.…”

Section: Methodsmentioning

confidence: 99%

“…Due to these features, LPS delivery is considered an attractive model of gram-negative sepsis. Post-ischemic delivery of LPS increases peripheral immune cells infiltration to the brain, induces microglial over-activation, and exacerbates ischemic brain injury in the mouse intraluminal middle cerebral artery occlusion (MCAO) model ( Sardari et al, 2020b ). Although the LPS exposure acts as an inflammatory stimulus, some studies with early post-ischemic LPS delivery have also reported neuroprotective effects of LPS in mice exposed to intraluminal MCAO ( Sardari et al, 2020a ).…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

N-Methyl-D-Aspartate Receptors Antagonist Prevents Secondary Ischemic Brain Injury Associated With Lipopolysaccharide-Induced Sepsis-Like State Presumably via Immunomodulatory Actions

Taheri

Sardari

Hermann

et al. 2022

Front. Cell. Neurosci.

View full text Add to dashboard Cite

Infection is a major reason for poor stroke outcomes, and sepsis is a major cause of stroke-elated deaths. We herein examined whether NMDA receptor blockade, which was reported to exert anti-inflammatory actions, protects against the deleterious consequences of lipopolysaccharide (LPS)-induced sepsis-like state in adult male NMRI mice exposed to transient intraluminal middle cerebral artery occlusion (MCAO). At 24 h post-ischemia, vehicle or Escherichia coli LPS (2 or 4 mg/kg) was intraperitoneally administered, whereas 30 min later vehicle or ketamine (10 mg/kg), which is a non-competitive NMDA receptor antagonist, was intraperitoneally applied. Delivery of LPS at a dosage of 4 mg/kg induced a sepsis-like state characterized by a rectal temperature reduction by ∼4.0°C, increased neurological deficits in Clark score, cylinder and open-field tests, increased brain infarct volume and reduced neuronal survival in the previously ischemic tissue. Notably, additional treatment with ketamine (10 mg/kg) significantly attenuated the sepsis-associated rectal temperature reduction by ∼1.5°C, reduced neurological deficits, reduced infarct volume, and promoted neuronal survival. Ketamine alone did not influence infarct volume or neurological deficits. Real-time PCR data analysis showed that GFAP, CD86, CD206, IL-1β, and IL-10 mRNA levels were significantly increased in ischemic brains of LPS-treated compared with vehicle-treated mice. Additional treatment with ketamine significantly decreased IL-1β and IL-10, but not GFAP, CD86, and CD206 mRNA levels. Our data show that ketamine at a dose that on its own does not confer neuroprotection reverses the adverse effects of LPS-induced sepsis-like state post-ischemia, presumably via immunomodulatory actions.

show abstract

Section: Discussionsupporting

confidence: 93%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

N-Methyl-D-Aspartate Receptors Antagonist Prevents Secondary Ischemic Brain Injury Associated With Lipopolysaccharide-Induced Sepsis-Like State Presumably via Immunomodulatory Actions

Taheri

Sardari

Hermann

et al. 2022

Front. Cell. Neurosci.

View full text Add to dashboard Cite

show abstract

“…These microglia responses mediate important physiological (e.g., fever) and behavioral (e.g., lethargy) components of sickness that promote survival [88]. This form of microglial activation is transient and occurs without causing overt neuropathology [41,[88][89][90][91][92]. Recent reports indicate that peripheral administration of LPS can cause transient BBB disruption and microbleeds in the brain [90,92].…”

Section: Peripheral Infectionmentioning

confidence: 99%

The semantics of microglia activation: neuroinflammation, homeostasis, and stress

Woodburn

Bollinger

Wohleb

2021

J Neuroinflammation

214

View full text Add to dashboard Cite

Microglia are emerging as critical regulators of neuronal function and behavior in nearly every area of neuroscience. Initial reports focused on classical immune functions of microglia in pathological contexts, however, immunological concepts from these studies have been applied to describe neuro-immune interactions in the absence of disease, injury, or infection. Indeed, terms such as ‘microglia activation’ or ‘neuroinflammation’ are used ubiquitously to describe changes in neuro-immune function in disparate contexts; particularly in stress research, where these terms prompt undue comparisons to pathological conditions. This creates a barrier for investigators new to neuro-immunology and ultimately hinders our understanding of stress effects on microglia. As more studies seek to understand the role of microglia in neurobiology and behavior, it is increasingly important to develop standard methods to study and define microglial phenotype and function. In this review, we summarize primary research on the role of microglia in pathological and physiological contexts. Further, we propose a framework to better describe changes in microglia1 phenotype and function in chronic stress. This approach will enable more precise characterization of microglia in different contexts, which should facilitate development of microglia-directed therapeutics in psychiatric and neurological disease.

show abstract

“…However, excessive neuroinflammation is believed to become a key factor contributing to further brain injury. Enhancement of neuroinflammation by injections of a lipopolysaccharide (LPS), bacterial cell wall endotoxin, augmented ischemic brain damage area [ 2 , 3 , 4 ]. Notably, after the onset of the first symptoms of stroke, an increase in the level of endotoxin was reported, presumably formed from Gram-negative bacteria of the respiratory, gastrointestinal, and urinary tracts [ 5 ].…”

Section: Introductionmentioning

confidence: 99%

Identifying the Involvement of Pro-Inflammatory Signal in Hippocampal Gene Expression Changes after Experimental Ischemia: Transcriptome-Wide Analysis

et al. 2021

View full text Add to dashboard Cite

Acute cerebral ischemia induces distant inflammation in the hippocampus; however, molecular mechanisms of this phenomenon remain obscure. Here, hippocampal gene expression profiles were compared in two experimental paradigms in rats: middle cerebral artery occlusion (MCAO) and intracerebral administration of lipopolysaccharide (LPS). The main finding is that 10 genes (Clec5a, CD14, Fgr, Hck, Anxa1, Lgals3, Irf1, Lbp, Ptx3, Serping1) may represent key molecular links underlying acute activation of immune cells in the hippocampus in response to experimental ischemia. Functional annotation clustering revealed that these genes built the same clusters related to innate immunity/immunity/innate immune response in all MCAO differentially expressed genes and responded to the direct pro-inflammatory stimulus group. The gene ontology enrichment and Kyoto Encyclopedia of Genes and Genomes pathway analyses also indicate that LPS-responding genes were the most abundant among the genes related to “positive regulation of tumor necrosis factor biosynthetic process”, “cell adhesion”, “TNF signaling pathway”, and “phagosome” as compared with non-responding ones. In contrast, positive and negative “regulation of cell proliferation” and “HIF-1 signaling pathway” mostly enriched with genes that did not respond to LPS. These results contribute to understanding genomic mechanisms of the impact of immune/inflammatory activation on expression of hippocampal genes after focal brain ischemia.

show abstract

Lipopolysaccharide-induced sepsis-like state compromises post-ischemic neurological recovery, brain tissue survival and remodeling via mechanisms involving microvascular thrombosis and brain T cell infiltration

Cited by 18 publications

References 41 publications

N-Methyl-D-Aspartate Receptors Antagonist Prevents Secondary Ischemic Brain Injury Associated With Lipopolysaccharide-Induced Sepsis-Like State Presumably via Immunomodulatory Actions

N-Methyl-D-Aspartate Receptors Antagonist Prevents Secondary Ischemic Brain Injury Associated With Lipopolysaccharide-Induced Sepsis-Like State Presumably via Immunomodulatory Actions

The semantics of microglia activation: neuroinflammation, homeostasis, and stress

Identifying the Involvement of Pro-Inflammatory Signal in Hippocampal Gene Expression Changes after Experimental Ischemia: Transcriptome-Wide Analysis

Contact Info

Product

Resources

About