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Journal of Physiotherapy Jul 2023
Topics: Humans; Brain Injuries, Traumatic; Physical Therapy Modalities
PubMed: 37286387
DOI: 10.1016/j.jphys.2023.05.015 -
Cell Communication and Signaling : CCS Sep 2023The poor prognosis of subarachnoid hemorrhage (SAH) is often attributed to neuroinflammation. The cGAS-STING axis, a cytoplasmic pathway responsible for detecting dsDNA,...
BACKGROUND
The poor prognosis of subarachnoid hemorrhage (SAH) is often attributed to neuroinflammation. The cGAS-STING axis, a cytoplasmic pathway responsible for detecting dsDNA, plays a significant role in mediating neuroinflammation in neurological diseases. However, the effects of inhibiting cGAS with the selective small molecule inhibitor RU.521 on brain injury and the underlying mechanisms after SAH are still unclear.
METHODS
The expression and microglial localization of cGAS following SAH were investigated with western blot analysis and immunofluorescent double-staining, respectively. RU.521 was administered after SAH. 2'3'-cGAMP, a second messenger converted by activated cGAS, was used to activate cGAS-STING. The assessments were carried out by adopting various techniques including neurological function scores, brain water content, blood-brain barrier permeability, western blot analysis, TUNEL staining, Nissl staining, immunofluorescence, morphological analysis, Morris water maze test, Golgi staining, CCK8, flow cytometry in the in vivo and in vitro settings.
RESULTS
Following SAH, there was an observed increase in the expression levels of cGAS in rat brain tissue, with peak levels observed at 24 h post-SAH. RU.521 resulted in a reduction of brain water content and blood-brain barrier permeability, leading to an improvement in neurological deficits after SAH. RU.521 had beneficial effects on neuronal apoptosis and microglia activation, as well as improvements in microglial morphology. Additionally, RU.521 prompted a shift in microglial phenotype from M1 to M2. We also noted a decrease in the production of pro-inflammatory cytokines TNF-α, IL-1β, and IL-6, and an increase in the level of the anti-inflammatory cytokine IL-10. Finally, RU.521 treatment was associated with improvements in cognitive function and an increase in the number of dendritic spines in the hippocampus. The therapeutic effects were mediated by the cGAS/STING/NF-κB pathway and were found to be abolished by 2'3'-cGAMP. In vitro, RU.521 significantly reduced apoptosis and neuroinflammation.
CONCLUSION
The study showed that SAH leads to neuroinflammation caused by microglial activation, which contributes to early brain injury. RU.521 improved neurological outcomes and reduced neuroinflammation by regulating microglial polarization through the cGAS/STING/NF-κB pathway in early brain injury after SAH. RU.521 may be a promising candidate for the treatment of neuroinflammatory pathology after SAH. Video Abstract.
Topics: Animals; Rats; Brain Injuries; Cytokines; Disease Models, Animal; Microglia; Neuroinflammatory Diseases; NF-kappa B; Rats, Sprague-Dawley; Signal Transduction; Subarachnoid Hemorrhage
PubMed: 37770901
DOI: 10.1186/s12964-023-01274-2 -
Critical Care (London, England) Jun 2023To describe the potential effects of ventilatory strategies on the outcome of acute brain-injured patients undergoing invasive mechanical ventilation. (Meta-Analysis)
Meta-Analysis
OBJECTIVE
To describe the potential effects of ventilatory strategies on the outcome of acute brain-injured patients undergoing invasive mechanical ventilation.
DESIGN
Systematic review with an individual data meta-analysis.
SETTING
Observational and interventional (before/after) studies published up to August 22nd, 2022, were considered for inclusion. We investigated the effects of low tidal volume Vt < 8 ml/Kg of IBW versus Vt > = 8 ml/Kg of IBW, positive end-expiratory pressure (PEEP) < or > = 5 cmHO and protective ventilation (association of both) on relevant clinical outcomes.
POPULATION
Patients with acute brain injury (trauma or haemorrhagic stroke) with invasive mechanical ventilation for ≥ 24 h.
MAIN OUTCOME MEASURES
The primary outcome was mortality at 28 days or in-hospital mortality. Secondary outcomes were the incidence of acute respiratory distress syndrome (ARDS), the duration of mechanical ventilation and the partial pressure of oxygen (PaO)/fraction of inspired oxygen (FiO) ratio.
RESULTS
The meta-analysis included eight studies with a total of 5639 patients. There was no difference in mortality between low and high tidal volume [Odds Ratio, OR 0.88 (95%Confidence Interval, CI 0.74 to 1.05), p = 0.16, I = 20%], low and moderate to high PEEP [OR 0.8 (95% CI 0.59 to 1.07), p = 0.13, I = 80%] or protective and non-protective ventilation [OR 1.03 (95% CI 0.93 to 1.15), p = 0.6, I = 11]. Low tidal volume [OR 0.74 (95% CI 0.45 to 1.21, p = 0.23, I = 88%], moderate PEEP [OR 0.98 (95% CI 0.76 to 1.26), p = 0.9, I = 21%] or protective ventilation [OR 1.22 (95% CI 0.94 to 1.58), p = 0.13, I = 22%] did not affect the incidence of acute respiratory distress syndrome. Protective ventilation improved the PaO/FiO ratio in the first five days of mechanical ventilation (p < 0.01).
CONCLUSIONS
Low tidal volume, moderate to high PEEP, or protective ventilation were not associated with mortality and lower incidence of ARDS in patients with acute brain injury undergoing invasive mechanical ventilation. However, protective ventilation improved oxygenation and could be safely considered in this setting. The exact role of ventilatory management on the outcome of patients with a severe brain injury needs to be more accurately delineated.
Topics: Humans; Respiration, Artificial; Tidal Volume; Respiratory Distress Syndrome; Oxygen; Brain Injuries
PubMed: 37280579
DOI: 10.1186/s13054-023-04509-3 -
CNS Neuroscience & Therapeutics Aug 2023Recently, human umbilical cord mesenchymal stem cell (HucMSC)-derived exosome is a new focus of research in neurological diseases. The present study was aimed to...
AIMS
Recently, human umbilical cord mesenchymal stem cell (HucMSC)-derived exosome is a new focus of research in neurological diseases. The present study was aimed to investigate the protective effects of HucMSC-derived exosome in both in vivo and in vitro TBI models.
METHODS
We established both mouse and neuron TBI models in our study. After treatment with HucMSC-derived exosome, the neuroprotection of exosome was investigated by the neurologic severity score (NSS), grip test score, neurological score, brain water content, and cortical lesion volume. Moreover, we determined the biochemical and morphological changes associated with apoptosis, pyroptosis, and ferroptosis after TBI.
RESULTS
We revealed that treatment of exosome could improve neurological function, decrease cerebral edema, and attenuate brain lesion after TBI. Furthermore, administration of exosome suppressed TBI-induced cell death, apoptosis, pyroptosis, and ferroptosis. In addition, exosome-activated phosphatase and tensin homolog-induced putative kinase protein 1/Parkinson protein 2 E3 ubiquitin-protein ligase (PINK1/Parkin) pathway-mediated mitophagy after TBI. However, the neuroprotection of exosome was attenuated when mitophagy was inhibited, and PINK1 was knockdown. Importantly, exosome treatment also decreased neuron cell death, suppressed apoptosis, pyroptosis, and ferroptosis and activated the PINK1/Parkin pathway-mediated mitophagy after TBI in vitro.
CONCLUSION
Our results provided the first evidence that exosome treatment played a key role in neuroprotection after TBI through the PINK1/Parkin pathway-mediated mitophagy.
Topics: Humans; Umbilical Cord; Mesenchymal Stem Cells; Exosomes; Apoptosis; Brain Injuries, Traumatic; Mice, Inbred ICR; Mitophagy; Signal Transduction; Protein Kinases; Ubiquitin-Protein Ligases; Neuroprotection; Pyroptosis; Ferroptosis; Mice; Animals
PubMed: 36890626
DOI: 10.1111/cns.14159 -
Der Nervenarzt Oct 2023Traumatic brain injury (TBI) describes parenchymal brain damage caused by external forces to the head. It has a massive personal and socioeconomic impact, as it is...
Traumatic brain injury (TBI) describes parenchymal brain damage caused by external forces to the head. It has a massive personal and socioeconomic impact, as it is a disease with high morbidity and mortality. Both young and old people are affected, as a result of traffic or sports accidents as well as due to falls at home. The term TBI encompasses various clinical pictures, differing considerably in cause, prognosis and therapy. What they all have in common is the pathophysiological cascade that develops immediately after the initial trauma and which can persist for several days and weeks. In this phase, medical treatment, whether surgical or pharmacological, attempts to reduce the consequences of the primary damage. The aim is to maintain adequate cerebral perfusion pressure and to reduce intracranial pressure.
Topics: Humans; Brain Injuries, Traumatic; Prognosis; Accidents; Intracranial Pressure; Cerebrovascular Circulation
PubMed: 37676293
DOI: 10.1007/s00115-023-01546-9 -
Cells Oct 2023Cerebral injury is a leading cause of long-term disability and mortality. Common causes include major cardiovascular events, such as cardiac arrest, ischemic stroke, and... (Review)
Review
Cerebral injury is a leading cause of long-term disability and mortality. Common causes include major cardiovascular events, such as cardiac arrest, ischemic stroke, and subarachnoid hemorrhage, traumatic brain injury, and neurodegenerative as well as neuroinflammatory disorders. Despite improvements in pharmacological and interventional treatment options, due to the brain's limited regeneration potential, survival is often associated with the impairment of crucial functions that lead to occupational inability and enormous economic burden. For decades, researchers have therefore been investigating adjuvant therapeutic options to alleviate neuronal cell death. Although promising in preclinical studies, a huge variety of drugs thought to provide neuroprotective effects failed in clinical trials. However, utilizing medical gases, noble gases, and gaseous molecules as supportive treatment options may offer new perspectives for patients suffering neuronal damage. This review provides an overview of current research, potentials and mechanisms of these substances as a promising therapeutic alternative for the treatment of cerebral injury.
Topics: Humans; Neuroprotection; Noble Gases; Gases; Neuroprotective Agents; Brain Injuries; Neurons
PubMed: 37887324
DOI: 10.3390/cells12202480 -
Neurotherapeutics : the Journal of the... Oct 2023Traumatic brain injury (TBI) results in both rapid and delayed brain damage. The speed, complexity, and persistence of TBI present large obstacles to drug development.... (Review)
Review
Traumatic brain injury (TBI) results in both rapid and delayed brain damage. The speed, complexity, and persistence of TBI present large obstacles to drug development. Preclinical studies from multiple laboratories have tested the FDA-approved anti-microbial drug minocycline (MINO) to treat traumatic brain injury. At concentrations greater than needed for anti-microbial action, MINO readily inhibits microglial activation. MINO has additional pleotropic effects including anti-inflammatory, anti-oxidant, and anti-apoptotic activities. MINO inhibits multiple proteins that promote brain injury including metalloproteases, caspases, calpain, and polyADP-ribose-polymerase-1. At these elevated doses, MINO is well tolerated and enters the brain even when the blood-brain barrier is intact. Most preclinical studies with a first dose of MINO at less than 1 h after injury have shown improved multiple outcomes after TBI. Fewer studies with more delayed dosing have yielded similar results. A small number of clinical trials for TBI have established the safety of MINO and suggested some drug efficacy. Studies are also ongoing that either improve MINO pharmacology or combine MINO with other drugs to increase its therapeutic efficacy against TBI. This review builds upon a previous, recent review by some of the authors (Lawless and Bergold, Neural Regen Res 17:2589-92, 2022). The present review includes the additional preclinical studies examining the efficacy of minocycline in preclinical TBI models. This review also includes recommendations for a clinical trial to test MINO to treat TBI.
Topics: Humans; Minocycline; Brain Injuries, Traumatic; Brain Injuries; Antioxidants
PubMed: 37721647
DOI: 10.1007/s13311-023-01426-9 -
Physiological Research Dec 2023Brain injury is a multifaceted condition arising from nonspecific damage to nervous tissue. The resulting cognitive developmental impairments reverberate through... (Review)
Review
Brain injury is a multifaceted condition arising from nonspecific damage to nervous tissue. The resulting cognitive developmental impairments reverberate through patients' lives, affecting their families, and even the broader economic landscape. The significance of early brain injury detection lies in its potential to stave off severe consequences and enhance the effectiveness of tailored therapeutic interventions. While established methods like neuroimaging and neurophysiology serve as valuable diagnostic tools, their demanding nature restricts their accessibility, particularly in scenarios such as small hospitals, nocturnal or weekend shifts, and cases involving unstable patients. Hence, there is a pressing need for more accessible and efficient diagnostic avenues. Among the spectrum of brain injuries, hypoxic-ischemic encephalopathy stands out as a predominant affliction in the pediatric population. Diagnosing brain injuries in newborns presents challenges due to the subjective nature of assessments like Apgar scores and the inherent uncertainty in neurological examinations. In this context, methods like magnetic resonance and ultrasound hold recommendations for more accurate diagnosis. Recognizing the potential of serum biomarkers derived from blood samples, this paper underscores their promise as a more expedient and resource-efficient means of assessing brain injuries. The review compiles current insights into serum biomarkers, drawing from experiments conducted on animal models as well as human brain pathologies. The authors aim to elucidate specific characteristics, temporal profiles, and the available corpus of experimental and clinical data for serum biomarkers specific to brain injuries. These include neuron-specific enolase (NSE), ubiquitin carboxy-terminal hydrolase L1 (UCH-L1), S100 calcium-binding protein beta (S100B), glial fibrillary acidic protein (GFAP), and high-mobility-group-protein-box-1 (HMGB1). This comprehensive endeavor contributes to advancing the understanding of brain injury diagnostics and potential avenues for therapeutic intervention.
Topics: Infant, Newborn; Humans; Child; Hypoxia-Ischemia, Brain; Brain Injuries; Biomarkers; Ubiquitin Thiolesterase
PubMed: 38165751
DOI: 10.33549/physiolres.935214 -
Frontiers in Immunology 2023Neonatal brain injury and associated inflammation is more common in males. There is a well-recognised difference in incidence and outcome of neonatal encephalopathy... (Review)
Review
Neonatal brain injury and associated inflammation is more common in males. There is a well-recognised difference in incidence and outcome of neonatal encephalopathy according to sex with a pronounced male disadvantage. Neurodevelopmental differences manifest from an early age in infancy with females having a lower incidence of developmental delay and learning difficulties in comparison with males and male sex has consistently been identified as a risk factor for cerebral palsy in epidemiological studies. Important neurobiological differences exist between the sexes with respect to neuronal injury which are especially pronounced in preterm neonates. There are many potential reasons for these sex differences including genetic, immunological and hormonal differences but there are limited studies of neonatal immune response. Animal models with induced neonatal hypoxia have shown various sex differences including an upregulated immune response and increased microglial activation in males. Male sex is recognized to be a risk factor for neonatal hypoxic ischemic encephalopathy (HIE) during the perinatal period and this review discusses in detail the sex differences in brain injury in preterm and term neonates and some of the potential new therapies with possible sex affects.
Topics: Animals; Male; Female; Sex Characteristics; Brain Injuries; Inflammation; Cerebral Palsy; Hypoxia-Ischemia, Brain
PubMed: 37954620
DOI: 10.3389/fimmu.2023.1243364 -
Acta Neuropathologica Dec 2023Lifelong brain health consequences of traumatic brain injury (TBI) include the risk of neurodegenerative disease. Up to one-third of women experience intimate partner...
Lifelong brain health consequences of traumatic brain injury (TBI) include the risk of neurodegenerative disease. Up to one-third of women experience intimate partner violence (IPV) in their lifetime, often with TBI, yet remarkably little is known about the range of autopsy neuropathologies encountered in IPV. We report a prospectively accrued case series from a single institution, the New York City Office of Chief Medical Examiner, evaluated in partnership with the Brain Injury Research Center of Mount Sinai, using a multimodal protocol comprising clinical history review, ex vivo imaging in a small subset, and comprehensive neuropathological assessment by established consensus protocols. Fourteen brains were obtained over 2 years from women with documented IPV (aged 3rd-8th decade; median, 4th) and complex histories including prior TBI in 6, nonfatal strangulation in 4, cerebrovascular, neurological, and/or psychiatric conditions in 13, and epilepsy in 7. At autopsy, all had TBI stigmata (old and/or recent). In addition, white matter regions vulnerable to diffuse axonal injury showed perivascular and parenchymal iron deposition and microgliosis in some subjects. Six cases had evidence of cerebrovascular disease (lacunes and/or chronic infarcts). Regarding neurodegenerative disease pathologies, Alzheimer disease neuropathologic change was present in a single case (8th decade), with no chronic traumatic encephalopathy neuropathologic change (CTE-NC) identified in any. Findings from this initial series then prompted similar exploration in an expanded case series of 70 archival IPV cases (aged 2nd-9th decade; median, 4th) accrued from multiple international institutions. In this secondary case series, we again found evidence of vascular and white matter pathologies. However, only limited neurodegenerative proteinopathies were encountered in the oldest subjects, none meeting consensus criteria for CTE-NC. These observations from this descriptive exploratory study reinforce a need to consider broad co-morbid and neuropathological substrates contributing to brain health outcomes in the context of IPV, some of which may be potentially modifiable.
Topics: Humans; Female; Neurodegenerative Diseases; Brain Injuries, Traumatic; Chronic Traumatic Encephalopathy; Brain; Intimate Partner Violence
PubMed: 37897548
DOI: 10.1007/s00401-023-02646-1