Proteostasis failure exacerbates neuronal circuit dysfunction and sleep impairments in Alzheimer’s disease

Molecular Neurodegeneration, Год журнала: 2023, Номер 18(1)

Опубликована: Апрель 21, 2023

Abstract Failed proteostasis is a well-documented feature of Alzheimer’s disease, particularly, reduced protein degradation and clearance. However, the contribution failed to neuronal circuit dysfunction an emerging concept in neurodegenerative research will prove critical understanding cognitive decline. Our objective convey disease progression with growing evidence for bidirectional relationship sleep disruption failure. Proteostasis tauopathy disrupts neurons that regulate sleep–wake cycle, which presents behavior as impaired slow wave rapid eye movement patterns. Subsequent loss further impairs Sleep defined seen early many disorders contributes memory impairments disease. Canonical pathological hallmarks, β-amyloid, tau, directly disrupt sleep, neurodegeneration locus coeruleus, hippocampal hypothalamic from tau proteinopathy causes circuitry sleep. Acting positive-feedback-loop, circadian rhythm then increase spread β-amyloid through proteasome, autophagy, unfolded response glymphatic This phenomenon extends beyond interactions impairment homeostasis TDP-43, α-synuclein, FUS, huntingtin proteins, implicating important consideration array diseases cases mixed neuropathology. Critically, dynamics this interaction environment are not fully elucidated deserving discussion research. Finally, we propose sleep-enhancing therapeutics potential interventions promoting healthy proteostasis, including clearance, mechanistically linking these processes. With clinical preclinical research, dynamic diagnostic therapeutic framework, informing precise single- combinatorial-treatments other brain disorders. Graphical

Язык: Английский

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Dexmedetomidine prevents septic myocardial dysfunction in rats via activation of α7nAChR and PI3K/Akt- mediated autophagy

Biomedicine & Pharmacotherapy, Год журнала: 2019, Номер 120, С. 109231 - 109231

Опубликована: Сен. 20, 2019

Dexmedetomidine (Dex) has been shown to elicit cardio-protective effects in sepsis. The aim of this study was investigate the role autophagy protective Dex and its possible mechanism vivo vitro.6-8-week-old male Wistar rats were performed cecal ligation puncture (CLP) administered 0.9% saline (CLP group), 50 μg/kg (Dex plus chloroquine (20 mg/kg; + CQ or 40 methyllycaconitin MLA 25 μM LY294002 group). After study, cardiac histology, function, level autophagy, cardiomyocytes apoptosis inflammatory mediators including protein IL-1β, IL-6, TNF-α measured. LPS induced-H9C2 treated with Dex, detected for cell apoptosis, cycle.CLP-induced sepsis resulted dysfunction, response. exhibited on myocardium by induction myocardial ameliorated LPS-induced blockade autophagic flux H9C2 cells. found significantly inhibit Dex-mediated protection inflammation. CLP combination MLA, an antagonist α7 nicotinic acetylcholine receptor (α7nAChR), decreased increased inflammation death, identifying α7nAchR involved pathway. In addition, we that PI3K/Akt pathway is convergent α7nAChR-mediated stimulation response.For first time, these data indicate central cardio-protection These observations provide foundation further may serve as basis innovative therapeutic strategies against septic dysfunction.

Язык: Английский

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The minimum effective concentration (MEC₉₀) of ropivacaine for ultrasound-guided supraclavicular brachial plexus block

Anaesthesia, Год журнала: 2016, Номер 71(6), С. 700 - 705

Опубликована: Март 4, 2016

The aim of this study was to determine the minimum effective concentration ropivacaine for ultrasound-guided supraclavicular brachial plexus block. Fifty-one patients undergoing arm surgery received double-injection block using 40 ml. administered each patient started at 0.225% and then depended on response previous one, based a biased coin design up-and-down sequential method. In case failure, increased by 0.025% w/v in next subject. successful block, randomised same or less. Success defined as complete sensory blockade 30 min after together with pain-free surgery. 90% subjects 0.257% (95% CI 0.241–0.280%).

Язык: Английский

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Neuroprotective effect of dexmedetomidine in a murine model of traumatic brain injury

Scientific Reports, Год журнала: 2018, Номер 8(1)

Опубликована: Март 15, 2018

No FDA approved pharmacological therapy is available that would reduce cell death following traumatic brain injury (TBI). Dexmedetomidine (Dex) a highly selective agonist of alpha-2 adrenergic receptors and has demonstrated neuroprotective effects in hippocampal slice cultures undergoing direct impact. However, no one tested whether Dex, addition to its sedative action, an animal model TBI. Thus, the present study, we investigated Dex on Mice received different doses (1, 10, or 100 µg/kg bodyweight, n = 10 each group) saline as control at 1 hour 12 hours The mice treated with lost less cortical tissue than mice. Further analysis found treatment reduced cortex hippocampus measured by Fluoro-Jade B (FJB) staining, prevented axonal degeneration detected immunostaining antibody against β-amyloid precursor protein (β-APP), protected synapses from elimination synaptophysin staining. Taken together, vivo murine TBI, dose not only lesion death, but also synaptic caused

Язык: Английский

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Dexmedetomidine Provides Protection Against Hippocampal Neuron Apoptosis and Cognitive Impairment in Mice with Alzheimer’s Disease by Mediating the miR-129/YAP1/JAG1 Axis

Molecular Neurobiology, Год журнала: 2020, Номер 57(12), С. 5044 - 5055

Опубликована: Авг. 24, 2020

Язык: Английский

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Administration of Dexmedetomidine inhibited NLRP3 inflammasome and microglial cell activities in hippocampus of traumatic brain injury rats

Bioscience Reports, Год журнала: 2018, Номер 38(5)

Опубликована: Сен. 19, 2018

The abnormally high nucleotide-binding oligomerization domain (NOD)-like receptor family pyrin containing 3 (NLRP3) inflammasome activity is a typical characteristic of traumatic brain injury (TBI). Dexmedetomidine (Dex) highly selective α-2 adrenergic agonist that inhibits the activation NLRP3. Thus, it was hypothesized Dex could attenuate TBI by inhibiting NLRP3 in hippocampus. Rats were subjected to controlled cortical impact method induce TBI, and treated with Dex. effect treatment on cognitive function, activity, microglial rat tissues assessed. administration improved performance rats Morris water maze (MWM) test, which associated increased neurone viability suppressed microglia activity. Moreover, inhibited neuroinflammation tissue as well expressions caspase-1. Additionally, inhibitor, BAY-11-7082 had synergistic NLRP3/caspase-1 axis improving TBI. findings outlined current study indicated improvement related its

Язык: Английский

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Protection of Dexmedetomidine Against Ischemia/Reperfusion-Induced Apoptotic Insults to Neuronal Cells Occurs Via an Intrinsic Mitochondria-Dependent Pathway

Journal of Cellular Biochemistry, Год журнала: 2016, Номер 118(9), С. 2635 - 2644

Опубликована: Дек. 17, 2016

Dexmedetomidine, an agonist of alpha2-adrenergic receptors, is used for critically ill patients to induce and maintain sedation analgesia. Brain ischemia/reperfusion (I/R) usually causes severe neuronal injuries intensive care unit patients. This study was aimed evaluate the effects dexmedetomidine on I/R-induced insults cells possible mechanisms. Treatment neuro-2a with did not affect cell viability but could protect against death. Separately, I/R-triggered shrinkage, DNA fragmentation, apoptosis in were alleviated by dexmedetomidine. As mechanisms, exposure substantially attenuated translocation Bax protein from cytosol mitochondria reduction mitochondrial membrane potential (MMP). Successively, decreased cytochrome c release cytoplasm consequent cascade activations caspases-9, -3, -6 I/R-treated cells. Interestingly, downregulating caspase-6 activity synergistically improved dexmedetomidine-induced defense The dexmedetomidine-involved neuroprotection further confirmed other NB41A3 significantly attenuating changes MMP, caspase-3 activation, apoptosis. Taken together, this has shown neuroprotective apoptotic via intrinsic Bax-mitochondria-cytochrome c-caspase protease pathway. J. Cell. Biochem. 118: 2635-2644, 2017. © 2016 Wiley Periodicals, Inc.

Язык: Английский

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RETRACTED: Effects of Dexmedetomidine on Postoperative Delirium and Expression of IL-1β, IL-6, and TNF-α in Elderly Patients After Hip Fracture Operation

Frontiers in Pharmacology, Год журнала: 2020, Номер 11

Опубликована: Май 12, 2020

Postoperative delirium (POD) is a common surgical complication in elderly patients. This study investigated the effects of dexmedetomidine on POD and pro-inflammatory markers patients with hip fracture.

Язык: Английский

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Dexmedetomidine effects in different experimental sepsis in vivo models

European Journal of Pharmacology, Год журнала: 2019, Номер 856, С. 172401 - 172401

Опубликована: Май 17, 2019

Язык: Английский

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Influence of dexmedetomidine on postoperative cognitive dysfunction in the elderly: A meta‐analysis of randomized controlled trials

Brain and Behavior, Год журнала: 2022, Номер 12(8)

Опубликована: Июль 10, 2022

Abstract Introduction Dexmedetomidine (Dex) is suggested to be neuroprotective. However, influence of Dex on postoperative cognitive dysfunction (POCD) in the elderly remains unknown. Methods We performed a meta‐analysis randomized controlled trials (RCTs) evaluate effect POCD. Relevant studies were obtained by search PubMed, Embase, and Cochrane's Library databases. A random‐effect model was used pool results. Results Fourteen RCTs including 1626 adults 60 years or older who received surgery with general anesthesia included. Because methodologically diverse scales for POCD, eight POCD diagnosed Mini‐Mental State Examination (MMSE) included meta‐analysis, while remaining six other qualitative synthesized. Pooled results MMSE showed that significantly reduced incidence (risk ratio: 0.47, 95% confidence interval: 0.37–0.60, p < 0.001) no significant heterogeneity ( I 2 = 0%) publication bias Egger's regression test 0.579). For scales, three them associated lower did not show difference. Conclusions risk patients receiving surgeries anesthesia, mainly MMSE. Based these findings, may considered as preventative measure patients.

Язык: Английский

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