Class I histone deacetylase inhibitor valproic acid reverses cognitive deficits in a mouse model of septic encephalopathy.
Wu Jing,Dong Lin,Zhang Mingqiang,Jia Min,Zhang Guangfeng,Qiu Lili,Ji Muhuo,Yang Jianjun
Neurochemical research
Accumulating evidence suggests that histone deacetylase inhibitor exert neuroprotective effects in animal models of neurological diseases. We investigated for the first time whether class I histone deacetylase inhibitor valproic acid (VPA) can reverse cognitive deficits in a mouse model of sepsis-associated encephalopathy (SAE). Moreover, the possible mechanisms of protection were also explored. A mouse model of SAE was induced in adult male mice by cecal ligation and puncture (CLP). Mice received an administration of saline or VPA (100 mg/kg) once daily for 14 consecutive days starting either immediately or 2 weeks after operation. Furthermore, the TrkB antagonist K252a was used in another group of experiment to investigate whether brain-derived neurotrophic factor (BDNF)-TrkB signaling pathway is involved in the protection of VPA. Our data suggested that CLP resulted in significant cognitive impairments accompanied by increased expressions in interleukin-1β and caspase-3, and decreased expressions in BDNF, phospho-TrkB (pTrkB), postsynaptic density 95, and synapses, which were reversed by VPA. However, TrkB antagonist K252a abolished the beneficial effects of VPA with regard to cognition and decreased pTrkB expression and synapses in the hippocampus. Taken together, the findings of the present study suggested chronic treatment with VPA reverses cognitive deficits through mechanisms probably via a reduction in inflammation and apoptosis in the brain, as well as the activation of the BDNF-TrkB signaling pathway in a mouse model of SAE.
10.1007/s11064-013-1159-0
Valproic acid attenuates the risk of acute respiratory failure in patients with subarachnoid hemorrhage.
Liao W-I,Chien W-C,Chung C-H,Wang J-C,Chung T-T,Chu S-J,Tsai S-H
QJM : monthly journal of the Association of Physicians
BACKGROUND:Valproic acid (VPA) has shown potent anti-inflammatory effect and attenuates acute lung injury. AIM:To determine whether the use of VPA is associated with a decreased risk of acute respiratory failure (ARF) in patients with subarachnoid hemorrhage (SAH). DESIGN:The Taiwan National Health Insurance Research Database was used to analyse all patients newly diagnosed with SAH from 2000 to 2010. The VPA users were matched for age, gender and index date in 1:2 ratios with randomly selected non-VPA users as a comparison group. METHODS:Multivariate Cox regression was used to identify the predictors of ARF and to compare the incidence rates of ARF among SAH patients using and not using VPA. RESULTS:The study cohort included 16 228 newly diagnosed SAH patients, from which 521 VPA users and 1042 matched non-VPA-exposed individuals were selected. In the VPA-treated cohort and the non-VPA-treated cohort, 117 and 289 patients developed ARF, respectively. Any use of VPA was associated with a 16% decreased risk of ARF requiring mechanical ventilation in 30-day tracking of the SAH patients (adjusted hazard ratio [HR], 0.840, 95% confidence interval [CI], 0.676-0.945). Age, sepsis and pneumonia were identified as independent predictors of ARF in patients with SAH. After stratification, VPA users showed a lower risk of ARF among SAH patients complicated with pneumonia compared with non-users of VPA (adjusted HR, 0.816, 95% CI, 0.652-0.921). CONCLUSIONS:Any use of VPA was associated with a reduced risk of ARF in patients with SAH. VPA may be beneficial for decreasing the risk of pneumonia-induced ARF in patients with SAH.
10.1093/qjmed/hcx199
The role of microglia activation in the development of sepsis-induced long-term cognitive impairment.
Michels Monique,Vieira Andriele S,Vuolo Francieli,Zapelini Hugo Galvane,Mendonça Bruna,Mina Francielle,Dominguini Diogo,Steckert Amanda,Schuck Patrícia Fernanda,Quevedo João,Petronilho Fabrícia,Dal-Pizzol Felipe
Brain, behavior, and immunity
Oxidative stress and inflammation is likely to be a major step in the development of sepsis-associated encephalopathy (SAE) and long-term cognitive impairment. To date, it is not known whether brain inflammation and oxidative damage are a direct consequence of systemic inflammation or whether these events are driven by brain resident cells, such as microglia. Therefore, the aim of this study is to evaluate the effect of minocycline on behavioral and neuroinflammatory parameters in rats submitted to sepsis. Male Wistar rats were subjected to sepsis by cecal ligation and puncture (CLP). The animals were divided into sham-operated (Sham+control), sham-operated plus minocycline (sham+MIN), CLP (CLP+control) and CLP plus minocycline (CLP+MIN) (100 μg/kg, administered as a single intracerebroventricular (ICV) injection). Some animals were killed 24h after surgery to assess the breakdown of the blood brain barrier, cytokine levels, oxidative damage to lipids (TBARS) and proteins in the hippocampus. Some animals were allowed to recover for 10 days when step-down inhibitory avoidance and open-field tasks were performed. Treatment with minocycline prevented an increase in markers of oxidative damage and inflammation in the hippocampus after sepsis. This was associated with an improvement in long-term cognitive performance. In conclusion, we demonstrated that the inhibition of the microglia by an ICV injection of minocycline was able to decrease acute brain oxidative damage and inflammation as well as long-term cognitive impairment in sepsis survivors.
10.1016/j.bbi.2014.07.002
Individual differences in the brain are associated with resilience versus susceptibility to lipopolysaccharide-induced memory impairment.
Tang Hui,Ji Muhuo,Zong Manman,Jia Min,Luo Dan,Zhou Zhiqiang,Yang Jianjun
Neuroscience letters
Sepsis impairs learning and memory function, yet marked interindividual variability exists in the degree to which sepsis compromises learning and memory function. Thus, testing resilience versus susceptibility to systemic inflammation induced-memory impairment and the underlying mechanism is needed. In the present study, we firstly used lipopolysaccharide (LPS) to induce memory impairment, and then evaluated cognitive function on days 4-7 after the first LPS challenge. Subjects' scores on both behavioral measures were subjected to a hierarchical cluster analysis, identifying two clusters that differed notably on the Y-maze and fear conditioning tests. This analysis divided these subjects into two groups, one cluster (13 of 34 subjects) displayed impaired working and associative memory, named "Susceptive". The remaining cluster (21 of 34 subjects) showed normal memory, named "Resilient". We have also included another group receiving normal saline to serve as the control group. The three groups underwent a battery of biochemical detections. In addition, we investigated whether the individual differences would disappear between the "Resilient" and "Susceptive" groups by using microglia inhibitor minocycline. We showed that as compared with the "Resilient" or control group, the "Susceptive" group was accompanied by increased tumor necrosis factor-alpha, interleukin-1beta (IL-1β), IL-6, and biomarkers of microglia activation ionized calcium binding adaptor molecule-1 and cluster of differentiation 68. Notably, after decreasing the activation of microglia, the differences in cognitive function between the "Resilient" and "Susceptive" groups disappeared. Collectively, our study suggests that individual differences in the brain are associated with resilience versus susceptibility to LPS-induced memory impairment.
10.1016/j.neulet.2017.10.064
Neuroinflammation-Induced Downregulation of Hippocampacal Neuregulin 1-ErbB4 Signaling in the Parvalbumin Interneurons Might Contribute to Cognitive Impairment in a Mouse Model of Sepsis-Associated Encephalopathy.
Gao Rong,Ji Mu-Huo,Gao Da-Peng,Yang Run-Hua,Zhang Shao-Gang,Yang Jian-Jun,Shen Jin-Chun
Inflammation
Sepsis-associated encephalopathy (SAE) is a common complication associated with poor prognosis in septic patients, but the underlying mechanism remains unclear. We hypothesized that disturbed neuregulin 1 (NRG1)-ErbB4 signaling in the parvalbumin interneurons was involved in sepsis-induced cognitive impairment in a mouse model of SAE. The SAE model was induced by cecal ligation/perforation (CLP). Animals were randomly divided into the following six groups: sham + vehicle group, sham + NRG1 group, CLP + vehicle group, CLP + NRG1 group, CLP + NRG1 + AG1478 (ErbB4 inhibitor) group, and CLP + minocycline group. Behavioral tests and in vivo electrophysiology were performed at the indicated time points. The brain tissues were harvested to determine the levels of hippocampcal cytokines, IBA1-positive cells, NRG1, ErbB4, and parvalbumin. In the present study, sepsis induced the anxiety-like behavior and hippocampal-dependent cognitive impairment, as reflected by significantly increased distance spent in the open field test and decreased freezing time to context in the fear conditioning test. The abnormal behavioral changes co-occurred with significant increases in hippocampal IBA1-positive cells, IL-1β and IL-6 levels, and decreased NRG1, ErbB4, parvalbumin expressions, and evoked gamma activity. NRG1 treatment attenuated the sepsis-induced cognitive impairment and the associated biochemical markers, which were abolished by AG1478 administration. Notably, minocycline treatment attenuated neuroinflammation and mimicked the beneficial effects of NRG1 treatment. In summary, we provided additional evidence that the disruption of NRG1-ErbB4 signaling in the parvalbumin interneurons mediated by neuroinflammation might lead to abnormal gamma oscillations and thus contribute to cognitive impairment in a mouse model of SAE.
10.1007/s10753-016-0484-2
Cognitive decline after sepsis.
Annane Djillali,Sharshar Tarek
The Lancet. Respiratory medicine
The modern era of sepsis management is characterised by a growing number of patients who survive in the short term and are discharged from hospital. Increasing evidence suggests that these survivors exhibit long-term neurological sequelae, particularly substantial declines in cognitive function. The exact prevalence and outcomes of these neuropsychological sequelae are unclear. The mechanisms by which sepsis induces cognitive dysfunction probably include vascular injuries and neuroinflammation that are mediated by systemic metabolism disorders and overwhelming inflammation, a disrupted blood-brain barrier, oxidative stress, and severe microglial activation, particularly within the limbic system. Interventions targeting the blood-brain barrier, glial activation, and oxidative stress have shown promise in prevention of cognitive dysfunction in various experimental models of sepsis. The next step should be to translate these favourable effects into positive clinical results.
10.1016/S2213-2600(14)70246-2
P2RX7 sensitizes Mac-1/ICAM-1-dependent leukocyte-endothelial adhesion and promotes neurovascular injury during septic encephalopathy.
Wang Huan,Hong Ling-Juan,Huang Ji-Yun,Jiang Quan,Tao Rong-Rong,Tan Chao,Lu Nan-Nan,Wang Cheng-Kun,Ahmed Muhammad M,Lu Ying-Mei,Liu Zhi-Rong,Shi Wei-Xing,Lai En-Yin,Wilcox Christopher S,Han Feng
Cell research
Septic encephalopathy (SE) is a critical factor determining sepsis mortality. Vascular inflammation is known to be involved in SE, but the molecular events that lead to the development of encephalopathy remain unclear. Using time-lapse in vivo two-photon laser scanning microscopy, we provide the first direct evidence that cecal ligation and puncture in septic mice induces microglial trafficking to sites adjacent to leukocyte adhesion on inflamed cerebral microvessels. Our data further demonstrate that septic injury increased the chemokine CXCL1 level in brain endothelial cells by activating endothelial P2RX7 and eventually enhanced the binding of Mac-1 (CD11b/CD18)-expressing leukocytes to endothelial ICAM-1. In turn, leukocyte adhesion upregulated endothelial CX3CL1, thereby triggering microglia trafficking to the injured site. The sepsis-induced increase in endothelial CX3CL1 was abolished in CD18 hypomorphic mutant mice. Inhibition of the P2RX7 pathway not only decreased endothelial ICAM-1 expression and leukocyte adhesion but also prevented microglia overactivation, reduced brain injury, and consequently doubled the early survival of septic mice. These results demonstrate the role of the P2RX7 pathway in linking neurovascular inflammation to brain damage in vivo and provide a rationale for targeting endothelial P2RX7 for neurovascular protection during SE.
10.1038/cr.2015.61
Melatonin alleviates brain injury in mice subjected to cecal ligation and puncture via attenuating inflammation, apoptosis, and oxidative stress: the role of SIRT1 signaling.
Zhao Lei,An Rui,Yang Yang,Yang Xiangmin,Liu Haixiao,Yue Liang,Li Xia,Lin Yan,Reiter Russel J,Qu Yan
Journal of pineal research
Sepsis is a systemic inflammatory response to infection that causes severe neurological complications. Previous studies have suggested that melatonin is protective during sepsis. Additionally, silent information regulator 1 (SIRT1) was reported to be beneficial in sepsis. However, the role of SIRT1 signaling in the protective effect of melatonin against septic encephalopathy remains unclear. This study aimed to investigate the role of SIRT1 in the protective effect of melatonin. EX527, a SIRT1 inhibitor, was used to reveal the role of SIRT1 in melatonin's action. Cecal ligation and puncture or sham operation was performed in male C57BL/6J mice. Melatonin was administrated intraperitoneally (30 mg/kg). The survival rate of mice was recorded for the 7-day period following the sham or CLP operation. The blood-brain barrier (BBB) integrity, brain water content, levels of inflammatory cytokines (TNF-α, IL-1β, and HMGB1), and the level of oxidative stress (superoxide dismutase (SOD), catalase (CAT), and malondialdehyde (MDA)) and apoptosis were assessed. The expression of SIRT1, Ac-FoxO1, Ac-p53, Ac-NF-κB, Bcl-2, and Bax was detected by Western blot. The results suggested that melatonin improved survival rate, attenuated brain edema and neuronal apoptosis, and preserved BBB integrity. Melatonin decreased the production of TNF-α, IL-1β, and HMGB1. Melatonin increased the activity of SOD and CAT and decreased the MDA production. Additionally, melatonin upregulated the expression of SIRT1 and Bcl-2 and downregulated the expression of Ac-FoxO1, Ac-p53, Ac-NF-κB, and Bax. However, the protective effects of melatonin were abolished by EX527. In conclusion, our results demonstrate that melatonin attenuates sepsis-induced brain injury via SIRT1 signaling activation.
10.1111/jpi.12254