Simvastatin Prevents Long-Term Cognitive Deficits in Sepsis Survivor Rats by Reducing Neuroinflammation and Neurodegeneration

Catalão, Carlos Henrique Rocha; Santos-Júnior, Nilton Nascimento; Costa, Luís Henrique Angenendt da; Souza, Anderson Oliveira; Cárnio, Evelin Capellari; Sebollela, Adriano; Alberici, Luciane C.; Rocha, Maria José Alves da

doi:10.1007/s12640-020-00222-z

Cited by 23 publications

(18 citation statements)

References 121 publications

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“…SAE patients present a hyperinflammatory response mainly in the hippocampus, which can be quantified by measuring the levels of the NLRP3 inflammasome, IL-1β, IL-6, and gliosis [ 2 , 27 , 31 , 49 ]. The tumor necrosis factor alpha (TNF-α) is another cytokine released in the brain when SAE occurs [ 27 , 31 , 50 ].…”

Section: Physiopathology Of Saementioning

confidence: 99%

“…Some molecules that are being postulated for SAE treatment are showing promising results in animal models. Rocha Catalão et al [ 49 ] showed that Simvastatin prevents long-term cognitive deficits in sepsis survivor rats, which is one of the main problems in sepsis and SAE survivor patients, by reducing neuroinflammation and neurodegeneration. They observed, in the hippocampus, a reduction of gliosis, nitrate, IL1-β, and IL-6 and overexpression of Bcl-2 protein levels, which was correlated with a decrease of apoptosis.…”

Section: Role Of Mirnas As a Potential Biomarker For Saementioning

confidence: 99%

“…They observed, in the hippocampus, a reduction of gliosis, nitrate, IL1-β, and IL-6 and overexpression of Bcl-2 protein levels, which was correlated with a decrease of apoptosis. Likewise, animals exposed to Simvastatin presented a better performance in tasks involving habituation, aversive and discriminative memory, and a reduction of neurodegeneration [ 49 ]. In another study, Zhang et al demonstrated the ability of amitriptyline to reduce sepsis-induced brain damage.…”

Section: Role Of Mirnas As a Potential Biomarker For Saementioning

confidence: 99%

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Role of microRNAs As Biomarkers in Sepsis-Associated Encephalopathy

et al. 2021

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Sepsis-associated encephalopathy (SAE) is a neurological complication of sepsis, characterized by brain dysfunction without any direct central nervous system infection. The diagnosis of SAE is currently a challenge. In fact, problems in making a diagnosis of SAE cause a great variability of incidence that can reach up to 70% of all septic patients. Even more, despite SAE is the most frequent type of encephalopathy occurring in critically ill patients, the molecular mechanisms that guide its progression have not been completely elucidated. On the other hand, miRNAs have proven to be excellent biomarkers for both diagnosis and prognosis, especially in brain pathologies because of their small size they can cross the blood–brain barrier easier than other biomolecules. The identification of new miRNAs as biomarkers may help to improve SAE diagnosis and prognosis and also to design new therapies for this clinical manifestation that produces diffuse cerebral dysfunction. This review is focused on SAE physiopathology and the need to have clear criteria for its diagnosis; thus, this work postulates some miRNA candidates to be used for SAE biomarkers because of their role in both, neurological damage and sepsis.

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Section: Physiopathology Of Saementioning

confidence: 99%

Section: Role Of Mirnas As a Potential Biomarker For Saementioning

confidence: 99%

Section: Role Of Mirnas As a Potential Biomarker For Saementioning

confidence: 99%

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Role of microRNAs As Biomarkers in Sepsis-Associated Encephalopathy

et al. 2021

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“…However, in a previous study, WB of the hippocampus and frontal cortex of septic rats that survived at 30 d after CLP, showed increased β-amyloid protein expression and decreased Synaptophysin expression [ 49 ]. Besides, in a study on simvastatin and rats that survived sepsis with long-term cognitive deficits suggested that the expression of Synaptophysin in the hippocampus of the CLP group decreased at 10 d after CLP [ 50 ]. This seems inconsistent with our results, but we speculate that it may be related to the short observation time point of this experiment.…”

Section: Discussionmentioning

confidence: 99%

Munc18-1 Contributes to Hippocampal Injury in Septic Rats Through Regulation of Syntanxin1A and Synaptophysin and Glutamate Levels

et al. 2022

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Sepsis-associated encephalopathy (SAE) is a diffuse brain dysfunction closely associated with mortality in the acute phase of sepsis. Abnormal neurotransmitters release, such as glutamate, plays a crucial role in the pathological mechanism of SAE. Munc18-1 is a key protein regulating neurotransmission. However, whether Munc18-1 plays a role in SAE by regulating glutamate transmission is still unclear. In this study, a septic rat model was established by the cecal ligation and perforation. We found an increase in the content of glutamate in the hippocampus of septic rat, the number of synaptic vesicles in the synaptic active area and the expression of the glutamate receptor NMDAR1. Meanwhile, it was found that the expressions of Munc18-1, Syntaxin1A and Synaptophysin increased, which are involved in neurotransmission. The expression levels of Syntaxin1A and Synaptophysin in hippocampus of septic rats decreased after interference using Munc18-1siRNA. We observed a decrease in the content of glutamate in the hippocampus of septic rats, the number of synaptic vesicles in the synaptic activity area and the expression of NMDAR1. Interestingly, it was also found that the down-regulation of Munc18-1 improved the vital signs of septic rats. This study shows that CLP induced the increased levels of glutamate in rat hippocampus, and Munc18-1 may participate in the process of hippocampal injury in septic rats by affecting the levels of glutamate via regulating Syntaxin1A and Synaptophysin. Munc18-1 may serve as a potential target for SAE therapy.

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“…Neuroinflammation is characterized by Aβ activated microglia which secretes neurotoxic mediators and proinflammatory cytokines to activate astrocytes to be neurotoxic [45,46]. Neuroinflammation causes neuronal death by neurotoxic astrocytes which upregulates complement cascade and neurotoxins [47,48]. Further, neuroinflammation can amplify itself by increasing tauopathy and Aβ deposition through microglia-secreted pro-inflammatory cytokines such as IL-6 and TNF-α [49].…”

Section: Discussionmentioning

confidence: 99%

Forsythoside B attenuates memory impairment and neuroinflammation via inhibition on NF-κB signaling in Alzheimer’s disease

Kong

Jiang

Wang

et al. 2020

J Neuroinflammation

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Background Neuroinflammation is a principal element in Alzheimer’s disease (AD) pathogenesis, so anti-inflammation may be a promising therapeutic strategy. Forsythoside B (FTS•B), a phenylethanoid glycoside isolated from Forsythiae fructus, has been reported to exert anti-inflammatory effects. However, no studies have reported whether the anti-inflammatory properties of FTS•B have a neuroprotective effect in AD. In the present study, these effects of FTS•B were investigated using amyloid precursor protein/presenilin 1 (APP/PS1) mice, BV-2 cells, and HT22 cells. Methods APP/PS1 mice were administered FTS•B intragastrically for 36 days. Behavioral tests were then carried out to examine cognitive functions, including the Morris water maze, Y maze, and open field experiment. Immunohistochemistry was used to analyze the deposition of amyloid-beta (Aβ), the phosphorylation of tau protein, and the levels of 4-hydroxynonenal, glial fibrillary acidic protein, and ionized calcium-binding adapter molecule 1 in the hippocampus. Proteins that showed marked changes in levels related to neuroinflammation were identified using proteomics and verified using enzyme-linked immunosorbent assay and western blot. BV-2 and HT22 cells were also used to confirm the anti-neuroinflammatory effects of FTS•B. Results In APP/PS1 mice, FTS•B counteracted cognitive decline, ameliorated the deposition of Aβ and the phosphorylation of tau protein, and attenuated the activation of microglia and astrocytes in the cortex and hippocampus. FTS•B affected vital signaling, particularly by decreasing the activation of JNK-interacting protein 3/C-Jun NH2-terminal kinase and suppressing WD-repeat and FYVE-domain-containing protein 1/toll-like receptor 3 (WDFY1/TLR3), further suppressing the activation of nuclear factor-κB (NF-κB) signaling. In BV-2 and HT22 cells, FTS•B prevented lipopolysaccharide-induced neuroinflammation and reduced the microglia-mediated neurotoxicity. Conclusions FTS•B effectively counteracted cognitive decline by regulating neuroinflammation via NF-κB signaling in APP/PS1 mice, providing preliminary experimental evidence that FTS•B is a promising therapeutic agent in AD treatment.

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Simvastatin Prevents Long-Term Cognitive Deficits in Sepsis Survivor Rats by Reducing Neuroinflammation and Neurodegeneration

Cited by 23 publications

References 121 publications

Role of microRNAs As Biomarkers in Sepsis-Associated Encephalopathy

Role of microRNAs As Biomarkers in Sepsis-Associated Encephalopathy

Munc18-1 Contributes to Hippocampal Injury in Septic Rats Through Regulation of Syntanxin1A and Synaptophysin and Glutamate Levels

Forsythoside B attenuates memory impairment and neuroinflammation via inhibition on NF-κB signaling in Alzheimer’s disease

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