Selective NLRP3 inflammasome inhibitor reduces neuroinflammation and improves long-term neurological outcomes in a murine model of traumatic brain injury

Neurobiology of Disease, Journal Year: 2018, Volume and Issue: 117, P. 15 - 27

Published: May 30, 2018

Language: Английский

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Current understanding of neuroinflammation after traumatic brain injury and cell-based therapeutic opportunities

Chinese Journal of Traumatology, Journal Year: 2018, Volume and Issue: 21(3), P. 137 - 151

Published: April 24, 2018

Traumatic brain injury (TBI) remains a major cause of death and disability worldwide. Increasing evidence indicates that TBI is an important risk factor for neurodegenerative diseases including Alzheimer's disease, Parkinson's chronic traumatic encephalopathy. Despite improved supportive rehabilitative care patients, unfortunately, all late phase clinical trials in have yet to yield safe effective neuroprotective treatment. The disappointing may be attributed variability treatment approaches heterogeneity the population patients as well race against time prevent or reduce inexorable cell death. not just acute event but disease. Among many mechanisms involved secondary after TBI, emerging preclinical studies indicate posttraumatic prolonged progressive neuroinflammation associated with neurodegeneration which treatable long initiating injury. This review provides overview recent understanding cell-based therapies target promote functional recovery TBI.

Language: Английский

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Biofluid biomarkers of traumatic brain injury

Brain Injury, Journal Year: 2017, Volume and Issue: 31(9), P. 1195 - 1203

Published: July 29, 2017

The purpose of this paper is to review the clinical and research utility applications blood, cerebrospinal fluid (CSF), cerebral microdialysis biomarkers in traumatic brain injury (TBI).Not applicable.A selective was performed on these biofluid TBI.Neurofilament heavy chain protein (NF-H), glial fibrillary acidic (GFAP), ubiquitin C-terminal hydrolase-L1 (UCHL1), neuron-specific enolase (NSE), myelin basic (MBP), tau, s100β blood are elevated during acute phase severe head trauma but have key limitations their mild TBI (mTBI). CSF currently provide best reflection central nervous system (CNS) pathobiological processes TBI. Both animal human studies demonstrated importance serial sampling biofluids suggest that may be better equipped characterize both severity temporal profiles.The identification could play a vital role identifying, diagnosing, treating underlying individual changes CNS-derived exosomes analyzed by ultra-high sensitivity detection methods potential identify for range time course.

Language: Английский

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The NLRP3 inflammasome in traumatic brain injury: potential as a biomarker and therapeutic target

Journal of Neuroinflammation, Journal Year: 2020, Volume and Issue: 17(1)

Published: April 6, 2020

There is a great clinical need to identify the underlying mechanisms, as well related biomarkers, and treatment targets, for traumatic brain injury (TBI). Neuroinflammation central pathophysiological feature of TBI. NLRP3 inflammasome activity necessary component innate immune response tissue damage, dysregulated has been implicated in number neurological conditions. This paper introduces its implication pathogenesis neuroinflammatory-related conditions, with particular focus on Although role TBI only recently identified, findings suggest that priming activation are upregulated following Moreover, recent studies utilizing specific inhibitors have provided further evidence this major driver neuroinflammation neurobehavioral disturbances In addition, there emerging circulating inflammasome-associated proteins may utility diagnostic biomarkers neuroinflammatory including Finally, novel promising areas research will be highlighted, potential involvement mild TBI, how factors such biological sex affect use biomarker platforms. Taken together, review highlights exciting target treatments ultimately used improve management.

Language: Английский

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The synapse in traumatic brain injury

Brain, Journal Year: 2020, Volume and Issue: 144(1), P. 18 - 31

Published: Sept. 10, 2020

Traumatic brain injury (TBI) is a leading cause of death and disability worldwide risk factor for dementia later in life. Research into the pathophysiology TBI has focused on impact neuron. However, recent advances have shown that major synapse structure function through combination immediate mechanical insult ensuing secondary processes, to loss. In this review, we highlight role with focus confluence multiple processes including excitotoxicity, inflammation oxidative stress. The primary triggers cascade events each these discuss complex interplay occurs at synapse. We also examine how impacted by traumatic axonal it may play spread tau after TBI. propose astrocytes crucial mediating both loss recovery. Finally, developments field molecular imaging, fluid biomarkers therapeutics. particular, our understanding diversity suggest new technology synaptome mapping prove useful identifying synapses are vulnerable or resistant

Language: Английский

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The complexity of neuroinflammation consequent to traumatic brain injury: from research evidence to potential treatments

Acta Neuropathologica, Journal Year: 2018, Volume and Issue: 137(5), P. 731 - 755

Published: Dec. 7, 2018

Language: Английский

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Role of pyroptosis in spinal cord injury and its therapeutic implications

Journal of Advanced Research, Journal Year: 2020, Volume and Issue: 28, P. 97 - 109

Published: Aug. 18, 2020

Currently, spinal cord injury (SCI) is a pathological incident that triggers several neuropathological conditions, leading to the initiation of neuronal damage with pro-inflammatory mediators' release. However, pyroptosis recognized as new programmed cell death mechanism regulated by stimulation caspase-1 and/or caspase-11/-4/-5 signaling pathways series inflammatory responses. Our current review concisely summarizes potential role pyroptosis-regulated in SCI, according molecular and pathophysiological mechanisms. This also highlights targeting inflammasome components its therapeutic implications for treatment SCI. Multiple pieces evidence have illustrated plays significant roles swelling, plasma membrane lysis, chromatin fragmentation intracellular factors including IL-18 IL-1β In addition, directly mediated recently discovered family pore-forming protein known GSDMD. Current investigations documented critical pathogenesis multiple neurological disorders well narrative article suggests inhibiting could be promising approach SCI near future.

Language: Английский

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A novel small molecular NLRP3 inflammasome inhibitor alleviates neuroinflammatory response following traumatic brain injury

Journal of Neuroinflammation, Journal Year: 2019, Volume and Issue: 16(1)

Published: April 11, 2019

Neuroinflammation is an essential player in many neurological diseases including traumatic brain injury (TBI). Recent studies have identified that inflammasome complexes are responsible for inflammatory responses pathological conditions. Inflammasomes intracellular multiprotein which regulate the innate immune response, activation of caspase-1, production pro-inflammatory cytokines IL-1β and IL-18, induction cell death (pyroptosis). Among family members, nucleotide-binding domain leucine-rich repeats protein 3 (NLRP3) most extensively studied its induced following TBI. As a novel target, drug development targeting formation NLRP3 prospective therapy We recently developed small molecule JC124 with specificity on inflammasome. In this study, we explored therapeutic value TBI treatment. Adult male Sprague-Dawley rats were subjected to moderate cortical impact injury. Following TBI, animals received 4 doses treatment first dose starting at 30 min, second 6 h after third fourth 24 or respectively. Animals sacrificed 2 days post-injury. Brain tissues processed either ELISA western blotting analysis histological examination assess degenerative neurons, acute response lesion volume. found post-injury significantly decreased number injury-induced degenerating injured brain, Injured treated also had reduced expression levels NLRP3, ASC, IL-1 beta, TNFα, iNOS, caspase-1. Our data suggest our inhibitor has specific anti-inflammatory effect protect

Language: Английский

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Aucubin alleviates oxidative stress and inflammation via Nrf2-mediated signaling activity in experimental traumatic brain injury

Journal of Neuroinflammation, Journal Year: 2020, Volume and Issue: 17(1)

Published: June 15, 2020

Abstract Background Aucubin (Au), an iridoid glycoside from natural plants, has antioxidative and anti-inflammatory bioactivities; however, its effects on a traumatic brain injury (TBI) model remain unknown. We explored the potential role of Au in H 2 O -induced oxidant damage primary cortical neurons weight-drop induced-TBI mouse model. Methods In vitro experiments, various concentrations (50 μg/ml, 100 or 200 μg/ml) were added culture medium at 0 h 6 after stimulated by (100 μM). After exposed for 12 h, collected western blot (WB), immunofluorescence, M29,79-dichlorodihydrofluorescein diacetate (DCFH-DA) staining. vivo (20 mg/kg 40 mg/kg) was administrated intraperitoneally 30 min, 24 48 modeling. Brain water content, neurological deficits, cognitive functions measured specific time, respectively. Cortical tissue around focal trauma WB, TdT-mediated dUTP Nick-End Labeling (TUNEL) staining, Nissl quantitative real time polymerase chain reaction (q-PCR), immunofluorescence/immunohistochemistry, enzyme linked immunosorbent assay (ELISA) 72 TBI. RNA interference experiments performed to determine nuclear factor erythroid-2 related (Nrf2) TBI mice with (40 treatment. Mice intracerebroventricularly lentivirus before establishment. The cortex obtained used WB q-PCR. Results enhanced translocation Nrf2 into nucleus, activated antioxidant enzymes, suppressed excessive generation reactive oxygen species (ROS), reduced cell apoptosis both experiments. TBI, markedly attenuated edema, histological damages, improved deficits. significantly high mobility group box 1 (HMGB1)-mediated aseptic inflammation. knockdown blunted neuroprotective Au. Conclusions Taken together, our data suggest that provides effect inhibiting oxidative stress inflammatory responses; mechanisms involve triggering Nrf2-induced system.

Language: Английский

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Carbogenic Nanozyme with Ultrahigh Reactive Nitrogen Species Selectivity for Traumatic Brain Injury

Nano Letters, Journal Year: 2019, Volume and Issue: 19(7), P. 4527 - 4534

Published: June 18, 2019

Reactive oxygen and nitrogen species (RONS), especially reactive (RNS) are intermediate products during incidence of nervous system diseases, showing continuous damage for traumatic brain injury (TBI). Here, we developed a carbogenic nanozyme, which shows an antioxidant activity 12 times higher than ascorbic acid (AA) behaves as multienzyme mimetics. Importantly, the nanozyme exhibits ultrahigh scavenging efficiency (∼16 AA) toward highly active RNS, such •NO ONOO– well traditional (ROS) including O2•–, H2O2, •OH. In vitro experiments show that neuron cells injured by H2O2 or lipopolysaccharide can be significantly recovered after treatment via all kinds RONS. Moreover, serve various enzyme mimetics eliminate harmful peroxide glutathione disulfide from mice, demonstrating its potential therapeutic acute TBI.

Language: Английский

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