Regulation of hippocampal neuronal apoptosis and autophagy in mice with sepsis‐associated encephalopathy by immunity‐related GTPase M1

Zhou, Ruixi; Li, Yu-Yao; Qu, Yi; Huang, Qun; Sun, Xiaojiang; Mu, Dezhi; Li, Xihong

doi:10.1111/cns.13229

Cited by 26 publications

(18 citation statements)

References 44 publications

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“…Multiple studies have con rmed the increased apoptosis in the hippocampus of mice with SAE [25], which is consistent with our results. And many drugs target on the decrease of apoptosis show signi cant brain-protective effects [9,25]. However, our study showed no bene ts of solely inhibiting apoptosis with Z-VAD-FMK or necroptosis with Nec-1.…”

Section: Discussionsupporting

confidence: 93%

“…Apoptosis and necroptosis are the main types of PCD that are involved in the pathology of anxiety and depression [24]. Multiple studies have con rmed the increased apoptosis in the hippocampus of mice with SAE [25], which is consistent with our results. And many drugs target on the decrease of apoptosis show signi cant brain-protective effects [9,25].…”

Section: Discussionsupporting

confidence: 92%

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Neuronal MD2 Induces Long-term Mental Impairments in Septic Mice by Facilitating Necroptosis and Apoptosis

Fan¹,

et al. 2021

Preprint

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Sepsis-associated encephalopathy (SAE) is a complication of sepsis that has high morbidity rates. Long-lasting depression is a major mental health disorder in patients with SAE that results in a substantial decrease in quality of life and economic burden. However, the underlying mechanism of SAE is unclear, and effective treatments are not available. In the current study, we explored the role of apoptosis and necroptosis related to depression in sepsis. In a mouse model of cecal ligation and puncture (CLP), we detected mental impairments by the open field test, elevated-plus maze and forced swimming test on the fourteenth day. Moreover, apoptosis- and necroptosis-associated proteins and morphological changes were examined in the hippocampus of the septic mice. These mice showed depression-like behaviors at 14 days after CLP, with substantial increases in neuronal apoptosis and necroptosis. Importantly, we found that apoptosis and necroptosis were related according to Ramsay’s rule in the brains of the septic mice. Inhibiting the function of MD2, the crosstalk mediator of apoptosis and necroptosis, in neurons effectively reduced neuronal loss and alleviated depression-like behaviors in the septic mice. These results suggest that neuronal death in the hippocampus contributes to the mental impairments in SAE and that inhibiting neuronal MD2 is a new strategy for treatment of mental health issues in sepsis by inhibiting necroptosis and apoptosis.

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Section: Discussionsupporting

confidence: 93%

Section: Discussionsupporting

confidence: 92%

Neuronal MD2 Induces Long-term Mental Impairments in Septic Mice by Facilitating Necroptosis and Apoptosis

Fan¹,

et al. 2021

Preprint

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“…The MAPK signaling pathway and NF- κ B signaling pathway are involved in various inflammatory diseases and contribute to the production of TNF- α , IL-1 β , and IL-6, hence reducing neuronal plasticity and neurogenesis [ 24 ]. These inflammatory signaling pathways were also demonstrated to be activated in the process of sepsis-associated encephalopathy [ 25 , 26 ]. Therefore, we detected the expression of inflammatory factors and the activation status of these signaling molecules in the hippocampus homogenate.…”

Section: Resultsmentioning

confidence: 99%

Senkyunolide I Protects against Sepsis-Associated Encephalopathy by Attenuating Sleep Deprivation in a Murine Model of Cecal Ligation and Puncture

Xie

Zhao

Zhu

et al. 2021

Oxidative Medicine and Cellular Longevity

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Sepsis may lead to sleep deprivation, which will promote the development of neuroinflammation and mediate the progression of sepsis-associated encephalopathy (SAE). Senkyunolide I, an active component derived from an herb medicine, has been shown to provide a sedative effect to improve sleep. However, its role in sepsis is unclear. The present study was performed to investigate whether Senkyunolide I protected against SAE in a murine model of cecal ligation and puncture (CLP). Here, we showed that Senkyunolide I treatment improved the 7-day survival rate and reduced the excessive release of cytokines including TNF-α, IL-6, and IL-1β. A fear conditioning test was performed, and the results showed that Senkyunolide I attenuated CLP-induced cognitive dysfunction. Senkyunolide I treatment also decreased the phosphorylation levels of inflammatory signaling proteins, including p-ERK, p-JNK, p-P38, and p-P65, and the level of inflammatory cytokines, including TNF-α, IL-6, and IL-1β, in the hippocampus homogenate. Sleep deprivation was attenuated by Senkyunolide I administration, as demonstrated by the modification of the BDNF and c-FOS expression. When sleep deprivation was induced manually, the protective effect of Senkyunolide I against inflammatory responses and cognitive dysfunction was reversed. Our data demonstrated that Senkyunolide I could protect against sepsis-associated encephalopathy in a murine model of sepsis via relieving sleep deprivation.

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“…This literature and our ndings suggest that increasing levels of autophagy may help mitigate sepsis-induced brain injury. However, a balance is needed: excessive autophagy can destroy cell homeostasis [37]. Further work should explore what autophagy levels may exert the best therapeutic effects.…”

Section: Discussionmentioning

confidence: 99%

CXCR5 Down-regulation Alleviates Cognitive Dysfunction in a Mouse Model of Sepsis-associated Encephalopathy: Potential Role of Neuronal Autophagy and the p38MAPK/NF-κB/STAT3 Signaling Pathway

Shen

Zhang

et al. 2021

Preprint

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BackgroundCognitive deficits are common in patients with sepsis. Previous studies in sepsis-associated encephalopathy (SAE) implicated the C-X-C chemokine receptor type (CXCR) 5. The present study used a mouse model of SAE to examine whether CXCR5 down-regulation could attenuate cognitive deficits.MethodsSepsis was induced in adult male C57BL/6J and CXCR5-/- mice by cecal ligation and puncture (CLP). At 14-18 days after surgery, animals were tested in a Morris water maze, followed by a fear conditioning test. Transmission electron microscopy of hippocampal sections was used to assess levels of autophagy. Primary microglial cultures challenged with lipopolysaccharide (LPS) were used to examine the effects of short interfering RNA targeting CXCR5, and to investigate the possible involvement of the p38MAPK/NF-κB/STAT3 signaling pathway.ResultsCLP impaired learning and memory and up-regulated CXCR5 in hippocampal microglia. CLP activated hippocampal autophagy, as reflected by increases in numbers of autophagic vacuoles, conversion of microtubule-associated protein 1 light chain 3 (LC3) from form I to form II, accumulation of beclin-1 and autophagy related gene-5, and a decrease in p62 expression. CLP also shifted microglial polarization to the M1 phenotype, and increased levels of IL-1β, IL-6 and phosphorylated p38MAPK. CXCR5 knockout further enhanced autophagy but partially reversed all the other CLP-induced effects, including cognitive deficits. Similar effects on autophagy and cytokine expression were observed after knocking down CXCR5 in LPS-challenged primary microglial cultures; this knockdown also partially reversed LPS-induced up-regulation of phosphorylated NF-κB and STAT3. The p38MAPK agonist P79350 partially reversed the effects of CXCR5 knockdown in microglial cultures.ConclusionsCXCR5 may act via p38MAPK/NF-κB/STAT3 signaling to inhibit hippocampal autophagy during sepsis and thereby contribute to cognitive dysfunction. Down-regulating CXCR5 can restore autophagy and mitigate the proinflammatory microenvironment in the hippocampus.

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Regulation of hippocampal neuronal apoptosis and autophagy in mice with sepsis‐associated encephalopathy by immunity‐related GTPase M1

Cited by 26 publications

References 44 publications

Neuronal MD2 Induces Long-term Mental Impairments in Septic Mice by Facilitating Necroptosis and Apoptosis

Neuronal MD2 Induces Long-term Mental Impairments in Septic Mice by Facilitating Necroptosis and Apoptosis

Senkyunolide I Protects against Sepsis-Associated Encephalopathy by Attenuating Sleep Deprivation in a Murine Model of Cecal Ligation and Puncture

CXCR5 Down-regulation Alleviates Cognitive Dysfunction in a Mouse Model of Sepsis-associated Encephalopathy: Potential Role of Neuronal Autophagy and the p38MAPK/NF-κB/STAT3 Signaling Pathway

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