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Alcohol-related cognitive impairment (ARCI) is highly prevalent among patients with alcohol abuse and dependence. The pathophysiology of ARCI, pivotal for refined therapeutic approaches, is not fully elucidated, posing a risk of progression to severe neurological sequelae such as Korsakoff's syndrome (KS) and Alcohol-Related Dementia (ARD). This study ventures into the underlying mechanisms of chronic alcohol-induced neurotoxicity, notably glutamate excitotoxicity and cytoskeletal disruption, and explores the therapeutic potential of Memantine, a non-competitive antagonist of the N-methyl-d-aspartate (NMDA) receptor known for its neuroprotective effect against excitotoxicity. Our investigation centers on the efficacy of Memantine in mitigating chronic alcohol-induced cognitive and hippocampal damages in vivo. Male C57BL/6J mice were subjected to 30 % (v/v, 6.0 g/kg) ethanol via intragastric administration alongside Memantine co-treatment (10 mg/kg/day, intraperitoneally) for six weeks. The assessment involved Y maze, Morris water maze, and novel object recognition tests to evaluate spatial and recognition memory deficits. Histopathological evaluations of the hippocampus were conducted to examine the extent of alcohol-induced morphological changes and the potential protective effect of Memantine. The findings reveal that Memantine significantly improves chronic alcohol-compromised cognitive functions and mitigates hippocampal pathological changes, implicating a moderating effect on the disassembly of actin cytoskeleton and microtubules in the hippocampus, induced by chronic alcohol exposure. Our results underscore Memantine's capability to attenuate chronic alcohol-induced cognitive and hippocampal morphological harm may partly through regulating cytoskeleton dynamics, offering valuable insights into innovative therapeutic strategies for ARCI.
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Alcohol-Related Brain Damage (ARBD) manifests predominantly as cognitive impairment and brain atrophy with the hippocampus showing particular vulnerability. Fasudil, a Rho kinase (ROCK) inhibitor, has established neuroprotective properties; however, its impact on alcohol-induced cognitive dysfunction and hippocampal structural damage remains unelucidated. This study probes Fasudil's neuroprotective potential and identifies its mechanism of action in an in vivo context. Male C57BL/6â¯J mice were exposed to 30% (v/v, 6.0â¯g/kg) ethanol by intragastric administration for four weeks. Concurrently, these mice received a co-treatment with Fasudil through intraperitoneal injections at a dosage of 10â¯mg/kg/day. Fasudil was found to mitigate alcohol-induced spatial and recognition memory deficits, which were quantified using Y maze, Morris water maze, and novel object recognition tests. Concurrently, Fasudil attenuated hippocampal structural damage prompted by chronic alcohol exposure. Notably, Fasudil moderated alcohol-induced disassembly of the actin cytoskeleton and microtubules-mechanisms central to the maintenance of hippocampal synaptic integrity. Collectively, our findings indicate that Fasudil partially reverses alcohol-induced cognitive and morphological detriments by modulating cytoskeletal dynamics, offering insights into potential therapeutic strategies for ARBD.
Assuntos
1-(5-Isoquinolinasulfonil)-2-Metilpiperazina , Disfunção Cognitiva , Etanol , Hipocampo , Camundongos Endogâmicos C57BL , Microtúbulos , Fármacos Neuroprotetores , Animais , 1-(5-Isoquinolinasulfonil)-2-Metilpiperazina/análogos & derivados , 1-(5-Isoquinolinasulfonil)-2-Metilpiperazina/farmacologia , Hipocampo/efeitos dos fármacos , Hipocampo/patologia , Hipocampo/metabolismo , Masculino , Camundongos , Disfunção Cognitiva/tratamento farmacológico , Disfunção Cognitiva/induzido quimicamente , Etanol/farmacologia , Fármacos Neuroprotetores/farmacologia , Microtúbulos/efeitos dos fármacos , Microtúbulos/metabolismo , Citoesqueleto de Actina/efeitos dos fármacos , Citoesqueleto de Actina/metabolismo , Modelos Animais de Doenças , Reconhecimento Psicológico/efeitos dos fármacosRESUMO
BACKGROUND: Alcohol abuse, a prevalent global health issue, is associated with the onset of cognitive impairment and neurodegeneration. Actin filaments (F-actin) and microtubules (MTs) polymerized from monomeric globular actin (G-actin) and tubulin form the structural basis of the neuronal cytoskeleton. Precise regulation of the assembly and disassembly of these cytoskeletal proteins, and their dynamic balance, play a pivotal role in regulating neuronal morphology and function. Nevertheless, the effect of prolonged alcohol exposure on cytoskeleton dynamics is not fully understood. This study investigates the chronic effects of alcohol on cognitive ability, neuronal morphology and cytoskeleton dynamics in the mouse hippocampus. METHODS: Mice were provided ad libitum access to 5% (v/v) alcohol in drinking water and were intragastrically administered 30% (v/v, 6.0 g/kg/day) alcohol for six weeks during adulthood. Cognitive functions were then evaluated using the Y maze, novel object recognition and Morris water maze tests. Hippocampal histomorphology was assessed through hematoxylin-eosin (HE) and Nissl staining. The polymerized and depolymerized states of actin cytoskeleton and microtubules were separated using two commercial assay kits and quantified by Western blot analysis. RESULTS: Mice chronically exposed to alcohol exhibited significant deficits in spatial and recognition memory as evidenced by behavioral tests. Histological analysis revealed notable hippocampal damage and neuronal loss. Decreased ratios of F-actin/G-actin and MT/tubulin, along with reduced levels of polymerized F-actin and MTs, were found in the hippocampus of alcohol-treated mice. CONCLUSIONS: Our findings suggest that chronic alcohol consumption disrupted the assembly of the actin cytoskeleton and MTs in the hippocampus, potentially contributing to the cognitive deficits and pathological injury induced by chronic alcohol intoxication.
Assuntos
Citoesqueleto de Actina , Etanol , Hipocampo , Microtúbulos , Animais , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Hipocampo/patologia , Microtúbulos/efeitos dos fármacos , Microtúbulos/metabolismo , Citoesqueleto de Actina/efeitos dos fármacos , Citoesqueleto de Actina/metabolismo , Masculino , Etanol/farmacologia , Etanol/administração & dosagem , Camundongos , Camundongos Endogâmicos C57BL , Depressores do Sistema Nervoso Central/farmacologia , Depressores do Sistema Nervoso Central/administração & dosagem , Modelos Animais de Doenças , Comportamento Animal/efeitos dos fármacosRESUMO
Background: Patients with Crohn's disease (CD) undergoing bowel resection often suffer from depression and acute pain, which severely impairs their recovery. We aimed to investigate the effects of S-ketamine preconditioning on postoperative depression in patients with CD undergoing a bowel resection with mild to moderate depression and to observe whether it can relieve postoperative pain and anti-inflammation. Methods: A total of 124 adult patients were randomized into one of the two groups. Patients in the S-ketamine group received a 0.25 mg/kg S-ketamine intravenous drip under general anesthesia induction, followed by a continuous infusion of S-ketamine with 0.12 mg/kg/h for more than 30 min through target-controlled infusion. Patients in the placebo group received 0.9% saline at an identical volume and rate. The primary outcome measure was the 17-item Hamilton depression Scale (HAMD-17). The secondary outcomes were scores on the following questionnaires: a nine-item patient health questionnaire (PHQ-9); a quality of recovery (QoR-15) form; and a numeric rating scale (NRS). Additional secondary outcomes included the levels of C-reactive protein (CRP) and interleukin 6 (IL-6) on postoperative days (PODs) 1, 3, and 5, the length of hospital stay, and opioid use throughout the hospital stay. Results: The scores of PHQ-9 and HAMD-17 in the S-ketamine group were lower than those in the placebo group on postoperative days (PODs) 1, 2, and 7 (p < 0.05). The scores of QoR-15 in the S-ketamine group were higher than those in the placebo group on postoperative days (PODs) 3 and 5 (p < 0.05). The NRS scores of PACU, postoperative days 1 and 2 in the S-ketamine group were lower than those in the placebo group (p < 0.05). There was no significant difference in the CRP and IL-6 levels on postoperative days (PODs) 1, 3, and 5, postoperative complications, and hospital stay between the two groups (p > 0.05). Conclusions: The trial indicated that the intraoperative administration of low-dose S-ketamine could alleviate mild-to-moderate depressive symptoms and postoperative pain in patients with Crohn's disease undergoing bowel resection without worsening their safety.
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Disrupted immune response is an important feature of many neurodegenerative conditions, including sepsis-associated cognitive impairment. Accumulating evidence has demonstrated that immune memory occurs in microglia, which has a significant impact on pathological hallmarks of neurological diseases. However, it remains unclear whether immune memory can cause subsequent alterations in the brain immune response and affect neurobehavioral outcomes in sepsis survivors. In the present study, mice received daily intraperitoneal injection of low-dose lipopolysaccharide (LPS, 0.1 mg/kg) for three consecutive days to induce immune memory (immune tolerance) and then were subjected to sham operation or cecal ligation and puncture (CLP) 9 months later, followed by a battery of neurobehavioral and biochemical studies. Here, we showed that repeated low-dose LPS injection-induced immune memory protected mice from sepsis-induced cognitive and affective impairments, which were accompanied by significantly decreased brain proinflammatory cytokines and immune response. In conclusion, our study suggests that modulation of brain immune responses by repeated LPS injections confers neuroprotective effects by preventing overactivated immune response in response to subsequent septic insult.
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Imunidade Inata/fisiologia , Lipopolissacarídeos/administração & dosagem , Lipopolissacarídeos/imunologia , Fármacos Neuroprotetores/imunologia , Sepse/imunologia , Animais , Ceco/lesões , Citocinas/sangue , Imunofluorescência , Ligadura/efeitos adversos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Fármacos Neuroprotetores/administração & dosagem , Teste de Campo Aberto , Punções/efeitos adversos , Sepse/sangueRESUMO
Neuroinflammation plays a key role in the progression of many neurodegenerative diseases, yet the underlying mechanism remains largely unexplored. Using an animal model of neuroinflammation induced by repeated lipopolysaccharide (LPS) injections, we found selectively reduced expression of parvalbumin (PV) but not somatostatin (SST) in the medial prefrontal cortex (mPFC). The reduced PV expression resulted in decreased intensities of vesicular GABA transporter and PV buttons, suggesting disinhibition in the mPFC. These further induced abnormal mPFC neural activities and consequently contributed to cognitive impairments. In addition, gamma oscillations supported by PV interneuron function were positively associated with time spent with the novel object in the novel object recognition test. Notably, down-regulation of neuroinflammation by microglia inhibitor minocycline or boosting gamma oscillations by dopamine 4 receptor agonist RO-10-5824 improved cognitive performance. In conclusion, our study proposes neural network disturbance as a likely mechanistic linker between neuroinflammation and cognitive impairments in neurodegeneration and possibly other psychiatric disorders.
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Disfunção Cognitiva , Parvalbuminas , Animais , Disfunção Cognitiva/induzido quimicamente , Interneurônios/metabolismo , Redes Neurais de Computação , Parvalbuminas/metabolismo , Córtex Pré-Frontal/metabolismoRESUMO
To improve light environment, photosynthetic capacity, and thus the yield of maize, the effects of directional planting on light distribution in canopy and photosynthetic characteristics of ear leaves, as well as the performance of PSII that closely related with photosynthetic characteristics and reflected by the rapid chlorophyll fluorescence kinetic curves were examined in Zhengdan 958 maize variety. The results showed that the orientation of leaves remarkably affected photosynthetically active radiation (PAR) interception of ear leaves, with PAR interception of ear leaves in southward treatment being 271.8% higher than that under northward treatment. The orientation of leaves affec-ted photosynthetic light use efficiency of ear leaves under high and low light conditions. The southward treatment increased net photosynthetic rate (Pn) under saturated light in ear leaves, indicating that the use efficiency to high light was enhanced in leaves of southward treatment. In contrast, the northward treatment increased the apparent quantum yield (α) of ear leaves, indicating leaves in southward treatment adapted the light-limited environment. During the early stage after anthesis, the performance of PSII electron donor side and electron acceptor side was significantly improved, and thus enhanced the performance of PSII reaction center (PIABS) and fluorescence photochemical quenching coefficient (Ψo) in ear leaves of southward treatment. The increase of quantum yield of electron transfer (φEo) indicated the enhancement of transfer performance of electrons from photosystem 2 (PSII) to photosystem 1 (PSI) in leaves of southward treatment. The photosynthetic performance of ear leaves showed a trend of southward > eastward > westward > northward during the early stage after anthesis. Forty days after anthesis, the use efficiency to high light decreased in ear leaves of southward treatment, but the ear leaves of southward treatment showed high use efficiency to low light, which changed the trend of photosynthetic performance of ear leaves to northward > westward > eastward > southward. In summary, northward and eastward treatments improved the light distribution in canopy, the PAR interception of ear leaves, the capacity of photosynthesis and dry matter production, and consequently increased the yield of summer maize.
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Fotossíntese , Folhas de Planta/fisiologia , Zea mays/fisiologia , Clorofila , Luz , Complexo de Proteína do Fotossistema I , Complexo de Proteína do Fotossistema IIRESUMO
In this paper, a susceptible-vaccinated-exposed-infectious-recovered (SVEIR) epidemic model for an infectious disease that spreads in the host population through horizontal transmission is investigated, assuming that the horizontal transmission is governed by an unspecified function f ( S , I ) . The role that temporary immunity (vaccinated-induced) and treatment of infected people play in the spread of disease, is incorporated in the model. The basic reproduction number R 0 is found, under certain conditions on the incidence rate and treatment function. It is shown that the model exhibits two equilibria, namely, the disease-free equilibrium and the endemic equilibrium. By constructing a suitable Lyapunov function, it is observed that the global asymptotic stability of the disease-free equilibrium depends on R 0 as well as on the treatment rate. If R 0 > 1 , then the endemic equilibrium is globally asymptotically stable with the help of the Li and Muldowney geometric approach applied to four dimensional systems. Numerical simulations are also presented to illustrate our main results.
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In this paper, we extend the model of Liu and Zhang (Math Comput Model 54:836-845, 2011) by incorporating three control terms and apply optimal control theory to the resulting model. Optimal control strategies are proposed to minimize both the disease burden and the intervention cost. We prove the existence and uniqueness of optimal control paths and obtain these optimal paths analytically using Pontryagin's Maximum Principle. We analyse our results numerically to compare various strategies of proposed controls. It is observed that implementation of three controls is most effective and less expensive among all the strategies. Thus, we conclude that in order to reduce tuberculosis threat all the three controls must be taken into consideration concurrently.
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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-1ß 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.
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Encefalite/patologia , Hipocampo/metabolismo , Hipocampo/fisiopatologia , Neuregulina-1/metabolismo , Receptor ErbB-4/metabolismo , Encefalopatia Associada a Sepse/fisiopatologia , Animais , Disfunção Cognitiva/tratamento farmacológico , Disfunção Cognitiva/etiologia , Modelos Animais de Doenças , Regulação para Baixo , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/uso terapêutico , Ritmo Gama , Hipocampo/química , Interneurônios/metabolismo , Camundongos , Parvalbuminas , Quinazolinas/farmacologia , Quinazolinas/uso terapêutico , Receptor ErbB-4/antagonistas & inibidores , Transdução de Sinais/efeitos dos fármacos , Tirfostinas/farmacologia , Tirfostinas/uso terapêuticoRESUMO
PURPOSE: The purpose of the present study was to test whether older red blood cells (RBCs) transfusion results in an increased risk of postoperative delirium (POD) and various in-hospital postoperative complications in elderly patients undergoing hip fracture surgery. MATERIALS AND METHODS: Patients (≥65 years) who underwent hip fracture surgery were enrolled, 179 patients were divided into two groups according to the storage time of the RBCs. The shorter storage time of RBCs transfusion group comprised patients who received RBCs ≤14 days old and the longer storage time of RBCs transfusion group comprised patients who received RBCs >14 days old. The blood samples were collected before anaesthesia induction, 4 and 24 h after RBCs transfusion for the determination of proinflammatory mediators, malondialdehyde, and superoxide dismutase activity. RESULTS: There was no difference in the baseline characteristics, the incidence of POD, and the in-hospital postoperative complications between the shorter storage time of RBCs transfusion group and the longer storage time of RBCs transfusion groups (P>0.05). Compared with the shorter storage time of RBCs transfusion group, the longer storage time of RBCs transfusion caused significantly longer duration of POD (P<0.05). There were significantly increased plasma levels of IL-8 and malondialdehyde at 24 h and IL-1ß at 4 h after RBCs transfusion in the POD group compared with the non-POD group (P<0.05). CONCLUSION: Transfusion of the longer storage RBCs is not associated with a higher incidence of POD or in-hospital postoperative complications, but with longer duration of POD in elderly patients undergoing hip fracture surgery.
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Artroplastia de Quadril/efeitos adversos , Delírio , Transfusão de Eritrócitos , Fraturas do Quadril/cirurgia , Malondialdeído/sangue , Complicações Pós-Operatórias/psicologia , Superóxido Dismutase/sangue , Idoso , Artroplastia de Quadril/psicologia , Biomarcadores/sangue , Delírio/sangue , Delírio/etiologia , Feminino , Hemoglobinas/análise , Fraturas do Quadril/complicações , Humanos , Masculino , Projetos Piloto , Complicações Pós-Operatórias/sangue , Estudos Prospectivos , Fatores de Tempo , Resultado do TratamentoRESUMO
INTRODUCTION: Accumulating evidence suggests that enhanced inflammatory responses contribute to the pathogenesis of postoperative cognitive dysfunction (POCD). Blood transfusion can trigger an enhancement of acute inflammatory responses. Therefore, we hypothesized that perioperative blood transfusion is associated with a higher risk of POCD in aged patients following total hip replacement surgery. MATERIAL AND METHODS: Patients older than 65 years undergoing elective total hip replacement surgery were enrolled from October 2011 to December 2012. Neurocognitive tests were evaluated at baseline and at 7 d after surgery by a Mini-Mental State Test. Multivariate logistic regression analysis was used to determine risk factors associated with POCD. RESULTS: Fifty-six patients (27.3%) developed POCD 7 d postoperatively. Patients who developed POCD were older, had a lower education level and preoperative hemoglobin concentration, had more blood loss, and had a lower body weight (p < 0.05). Patients with POCD were more likely to receive red blood cells (RBCs) transfusion (51.8% versus 31.5%; p < 0.05). A multivariable logistic regression model identified older age, lower education level, and perioperative blood transfusion of more than 3 units as independent risk factors for POCD 7 d postoperatively. CONCLUSION: Our data suggested that perioperative blood transfusion of more than 3 units of RBCs is an independent risk factor for POCD in aged patients following total hip replacement surgery.
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Artroplastia de Quadril/efeitos adversos , Transtornos Cognitivos/etiologia , Reação Transfusional , Idoso , Feminino , Humanos , MasculinoRESUMO
Valproic acid (VPA) has been shown to exert anti-inflammatory and antioxidant effects in a range of diseases including septic shock. However, the effects of VPA on lipopolysaccharide (LPS)-induced acute lung injury (ALI) remains not well understood. We found that VPA pretreatment attenuated the LPS-induced ALI, as evidenced by the reduced histological scores, myeloperoxidase activity, and wet-to-dry weight ratio in the lung tissues. This was accompanied by the downregulated nuclear factor kappa B (NF-κB) p65, nitric oxide, and inducible nitric oxide synthase in the lung tissues and the decreased levels of tumor necrosis factor alpha and interleukin-1ß in the bronchoalveolar lavage fluid. Furthermore, VPA reduced the nuclear histone deacetylase (HDAC)3 expression whereas increased the cytoplasmic HDAC3 expression. Our results suggested that VPA attenuates the LPS-induced ALI via inhibiting the NF-κB activation probably through a mechanism depending on HDAC3 redistribution.
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Lesão Pulmonar Aguda/tratamento farmacológico , Anti-Inflamatórios/uso terapêutico , Histona Desacetilases/metabolismo , Fator de Transcrição RelA/metabolismo , Ácido Valproico/uso terapêutico , Animais , Antioxidantes/uso terapêutico , Líquido da Lavagem Broncoalveolar , Regulação para Baixo , Histona Desacetilases/biossíntese , Inflamação/tratamento farmacológico , Inflamação/imunologia , Interleucina-1beta/biossíntese , Lipopolissacarídeos , Pulmão/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Infiltração de Neutrófilos/efeitos dos fármacos , Óxido Nítrico/biossíntese , Óxido Nítrico Sintase Tipo II/biossíntese , Peroxidase/metabolismo , Sepse/tratamento farmacológico , Fator de Transcrição RelA/biossíntese , Fator de Necrose Tumoral alfa/biossínteseRESUMO
OBJECTIVE: To investigate the effects of dexmedetomidine combined with fentanyl in patients undergoing anesthesia induction by sevoflurane. METHOD: Eighty patients for elective endotracheal intubation under general anesthesia operations were randomly and double-blindly divided into Dex combined with fentanyl group (Group DF) and the fentanyl group (Group F) from April 2011 to September 2011 at the Fourth Affiliated Hospital of Harbin Medical University, and there were 40 cases in each group. The investigation was approved by all the patients and by the Ethics Committee of the hospital. In group DF, each patient was pumped in the 0.5 µg/kg Dex by vein before 10 minutes of anesthesia induction and group F were given the same amount of normal saline, and tidal volume method was used to induce anesthesia of sevoflurane. All the patients were given 2 µg/kg fentanyl and 0.1 mg/kg vecuronium by tracheal intubation and the MAP and HR and adverse reactions were observed before anesthesia induction (T(0)), before endotracheal intubation (T(1)), at the moment of tracheal intubation (T(2)), after 1 minutes of tracheal intubation (T(3)), after 3 minutes of tracheal intubation (T(4)) and after 5 minutes of tracheal intubation (T(5)). RESULT: The loss of eyelash reflex time of group DF is shorter (P < 0.05), adverse reaction is less (P < 0.05) and the number of adding atropine case is higher than that of group F (P < 0.05), the MAP of the two groups after induction of other moments are lower than that of T(0) (P < 0.05); MAP of group F at T(1) is lower than that of T(0), T(2), T(3) and group DF (P < 0.05); T(1) of group DF is lower than that of T(0) (P < 0.05), the HR after induction of group DF is lower than that of T(0) and F group (P < 0.05), and that of T(2) and T(4) are higher than that of T(1) (P < 0.05); HR of group F at T(1) is lower than that of T(2) and T(3) (P < 0.05). CONCLUSION: Dexmedetomidine in combination with fentanyl can inhibit stress response of tracheal intubation of sevoflurane induction efficiently and stabilize hemodynamics.