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Ferroptosis is a caspase-independent, iron-dependent form of regulated necrosis extant in traumatic brain injury, Huntington disease, and hemorrhagic stroke. It can be activated by cystine deprivation leading to glutathione depletion, the insufficiency of the antioxidant glutathione peroxidase-4, and the hemolysis products hemoglobin and hemin. A cardinal feature of ferroptosis is extracellular signal-regulated kinase (ERK)1/2 activation culminating in its translocation to the nucleus. We have previously confirmed that the mitogen-activated protein (MAP) kinase kinase (MEK) inhibitor U0126 inhibits persistent ERK1/2 phosphorylation and ferroptosis. Here, we show that hemin exposure, a model of secondary injury in brain hemorrhage and ferroptosis, activated ERK1/2 in mouse neurons. Accordingly, MEK inhibitor U0126 protected against hemin-induced ferroptosis. Unexpectedly, U0126 prevented hemin-induced ferroptosis independent of its ability to inhibit ERK1/2 signaling. In contrast to classical ferroptosis in neurons or cancer cells, chemically diverse inhibitors of MEK did not block hemin-induced ferroptosis, nor did the forced expression of the ERK-selective MAP kinase phosphatase (MKP)3. We conclude that hemin or hemoglobin-induced ferroptosis, unlike glutathione depletion, is ERK1/2-independent. Together with recent studies, our findings suggest the existence of a novel subtype of neuronal ferroptosis relevant to bleeding in the brain that is 5-lipoxygenase-dependent, ERK-independent, and transcription-independent. Remarkably, our unbiased phosphoproteome analysis revealed dramatic differences in phosphorylation induced by two ferroptosis subtypes. As U0126 also reduced cell death and improved functional recovery after hemorrhagic stroke in male mice, our analysis also provides a template on which to build a search for U0126's effects in a variant of neuronal ferroptosis.SIGNIFICANCE STATEMENT Ferroptosis is an iron-dependent mechanism of regulated necrosis that has been linked to hemorrhagic stroke. Common features of ferroptotic death induced by diverse stimuli are the depletion of the antioxidant glutathione, production of lipoxygenase-dependent reactive lipids, sensitivity to iron chelation, and persistent activation of extracellular signal-regulated kinase (ERK) signaling. Unlike classical ferroptosis induced in neurons or cancer cells, here we show that ferroptosis induced by hemin is ERK-independent. Paradoxically, the canonical MAP kinase kinase (MEK) inhibitor U0126 blocks brain hemorrhage-induced death. Altogether, these data suggest that a variant of ferroptosis is unleashed in hemorrhagic stroke. We present the first, unbiased phosphoproteomic analysis of ferroptosis as a template on which to understand distinct paths to cell death that meet the definition of ferroptosis.
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Ferroptose , Acidente Vascular Cerebral Hemorrágico , Animais , Antioxidantes/metabolismo , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Glutationa/metabolismo , Hemina/metabolismo , Hemina/farmacologia , Hemoglobinas/metabolismo , Hemorragias Intracranianas/metabolismo , Ferro/metabolismo , Masculino , Camundongos , Quinases de Proteína Quinase Ativadas por Mitógeno/metabolismo , Necrose/metabolismo , Neurônios/metabolismo , FosforilaçãoRESUMO
Stroke is a severe and life-threatening disease, necessitating more research on new treatment strategies. Infiltrated T lymphocytes, an essential adaptive immune cell with extensive effector function, are crucially involved in post-stroke inflammation. Immediately after the initiation of the innate immune response triggered by microglia/macrophages, the adaptive immune response associated with T lymphocytes also participates in the complex pathophysiology of stroke and partially informs the outcome of stroke. Preclinical and clinical studies have revealed the conflicting roles of T cells in post-stroke inflammation and as potential therapeutic targets. Therefore, exploring the mechanisms that underlie the adaptive immune response associated with T lymphocytes in stroke is essential. The T-cell receptor (TCR) and its downstream signaling regulate T lymphocyte differentiation and activation. This review comprehensively summarizes the various molecules that regulate TCR signaling and the T-cell response. It covers both the co-stimulatory and co-inhibitory molecules and their roles in stroke. Because immunoregulatory therapies targeting TCR and its mediators have achieved great success in some proliferative diseases, this article also summarizes the advances in therapeutic strategies related to TCR signaling in lymphocytes after stroke, which can facilitate translation.
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Receptores de Antígenos de Linfócitos T , Linfócitos T , Humanos , Transdução de Sinais , Ativação Linfocitária , InflamaçãoRESUMO
We rely on vision more than on any other sense to obtain information about our environment. Hence, the loss or even impairment of vision profoundly affects our quality of life. Diet or food components have already demonstrated beneficial effects on the development of retinal diseases. Recently, there has been a growing interest in resources from marine animals and plants for the prevention of retinal diseases through nutrition. Especially fish intake and omega-3 fatty acids have already led to promising results, including associations with a reduced incidence of retinal diseases. However, the underlying molecular mechanisms are insufficiently explained. The aim of this review was to summarize the known mechanistic effects of marine resources on the pathophysiological processes in retinal diseases. We performed a systematic literature review following the PRISMA guidelines and identified 107 studies investigating marine resources in the context of retinal diseases. Of these, 46 studies described the underlying mechanisms including anti-inflammatory, antioxidant, antiangiogenic/vasoprotective, cytoprotective, metabolic, and retinal function effects, which we critically summarize. We further discuss perspectives on the use of marine resources for human nutrition to prevent retinal diseases with a particular focus on regulatory aspects, health claims, safety, and bioavailability.
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Ácidos Graxos Ômega-3 , Doenças Retinianas , Animais , Antioxidantes/metabolismo , Ácidos Graxos Ômega-3/metabolismo , Ácidos Graxos Ômega-3/farmacologia , Ácidos Graxos Ômega-3/uso terapêutico , Humanos , Qualidade de Vida , Retina/metabolismo , Doenças Retinianas/metabolismo , Doenças Retinianas/prevenção & controleRESUMO
Fucoidans are algal polysaccharides that exhibit protective properties against oxidative stress. The aim of this study was to investigate different fucoidans from brown seaweeds for their ability to protect against iron-dependent oxidative stress (ferroptosis), a main hallmark of retinal and brain diseases, including hemorrhage. We investigated five new high-molecular weight fucoidan extracts from Fucus vesiculosus, F. serratus, and F. distichus subsp. evanescens, a previously published Laminaria hyperborean extract, and commercially available extracts from F. vesiculosus and Undaria pinnatifida. We induced oxidative stress by glutathione depletion (erastin) and H2O2 in four retinal and neuronal cell lines as well as primary cortical neurons. Only extracts from F. serratus, F. distichus subsp. evanescens, and Laminaria hyperborea were partially protective against erastin-induced cell death in ARPE-19 and OMM-1 cells, while none of the extracts showed beneficial effects in neuronal cells. Protective fucoidans also attenuated the decrease in protein levels of the antioxidant enzyme GPX4, a key regulator of ferroptosis. This comprehensive analysis demonstrates that the antioxidant abilities of fucoidans may be cell type-specific, besides depending on the algal species and extraction method. Future studies are needed to further characterize the health-benefiting effects of fucoidans and to determine the exact mechanism underlying their antioxidative abilities.
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Antioxidantes/farmacologia , Fucus , Laminaria , Polissacarídeos/farmacologia , Organismos Aquáticos , Morte Celular/efeitos dos fármacos , Linhagem Celular/efeitos dos fármacos , Humanos , Peróxido de Hidrogênio , Ferro , Neurônios , Estresse Oxidativo/efeitos dos fármacos , RetinaRESUMO
The original version of the article unfortunately contained an error in the unit of the protein concentrations under 'Stereotactic Intraparenchymal Injections' subsection in 'Methods' section.
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Pigment epithelium-derived factor (PEDF) is a neurotrophic factor with neuroprotective, antiangiogenic, and antipermeability effects. In the brain, blood-brain barrier (BBB) function is essential for homeostasis. Its impairment plays a crucial role in the pathophysiology of many neurological diseases, including ischemic stroke. We investigated (a) whether PEDF counteracted vascular endothelial growth factor (VEGF)-induced BBB disruption in the mouse brain, (b) the time course and route of BBB permeability and the dynamics of PEDF expression after cerebral ischemia, and (c) whether intraventricular infusion of PEDF ameliorated brain ischemia by reducing BBB impairment. C57Bl6/N mice received intraparenchymal injections of CSF, VEGF, or a combination of VEGF and PEDF. PEDF increased paracellular but not transcellular BBB integrity as indicated by an increase in the tight junction protein claudin-5. In another group of mice undergoing 60-min middle cerebral artery occlusion (MCAO), transcellular BBB permeability (fibrinogen staining in the absence of a loss of claudin-5) increased as early as 6 h after reperfusion. PEDF immunofluorescence increased at 24 h, which paralleled with a decreased paracellular BBB permeability (claudin-5). PEDF after MCAO originated from the blood stream and endogenous pericytes. In the third experiment, the intraventricular infusion of PEDF decreased edema and cell death after MCAO, potentially mediated by the improvement of the paracellular route of BBB permeability (claudin-5) in the absence of an amelioration of Evans Blue extravasation. Together, our data suggest that PEDF improves BBB function after cerebral ischemia by affecting the paracellular but not the transcellular route. However, further quantitative data of the different routes of BBB permeability will be required to validate our findings.
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Barreira Hematoencefálica/efeitos dos fármacos , Proteínas do Olho/farmacologia , Ataque Isquêmico Transitório/terapia , Fatores de Crescimento Neural/farmacologia , Fármacos Neuroprotetores/farmacologia , Serpinas/farmacologia , Animais , Barreira Hematoencefálica/lesões , Barreira Hematoencefálica/metabolismo , Claudina-5/metabolismo , Modelos Animais de Doenças , Proteínas do Olho/uso terapêutico , Ataque Isquêmico Transitório/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Fatores de Crescimento Neural/uso terapêutico , Fármacos Neuroprotetores/uso terapêutico , Serpinas/uso terapêutico , Fator A de Crescimento do Endotélio Vascular/farmacologiaRESUMO
BACKGROUND AND PURPOSE: Intracerebral hemorrhage leads to disability or death with few established treatments. Adverse outcomes after intracerebral hemorrhage result from irreversible damage to neurons resulting from primary and secondary injury. Secondary injury has been attributed to hemoglobin and its oxidized product hemin from lysed red blood cells. The aim of this study was to identify the underlying cell death mechanisms attributable to secondary injury by hemoglobin and hemin to broaden treatment options. METHODS: We investigated cell death mechanisms in cultured neurons exposed to hemoglobin or hemin. Chemical inhibitors implicated in all known cell death pathways were used. Identified cell death mechanisms were confirmed using molecular markers and electron microscopy. RESULTS: Chemical inhibitors of ferroptosis and necroptosis protected against hemoglobin- and hemin-induced toxicity. By contrast, inhibitors of caspase-dependent apoptosis, protein or mRNA synthesis, autophagy, mitophagy, or parthanatos had no effect. Accordingly, molecular markers of ferroptosis and necroptosis were increased after intracerebral hemorrhage in vitro and in vivo. Electron microscopy showed that hemin induced a necrotic phenotype. Necroptosis and ferroptosis inhibitors each abrogated death by >80% and had similar therapeutic windows in vitro. CONCLUSIONS: Experimental intracerebral hemorrhage shares features of ferroptotic and necroptotic cell death, but not caspase-dependent apoptosis or autophagy. We propose that ferroptosis or necroptotic signaling induced by lysed blood is sufficient to reach a threshold of death that leads to neuronal necrosis and that inhibition of either of these pathways can bring cells below that threshold to survival.
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Apoptose , Hemorragia Cerebral/metabolismo , Hemina/metabolismo , Hemoglobinas/metabolismo , Necrose/metabolismo , Neurônios/metabolismo , Animais , Células Cultivadas , Modelos Animais de Doenças , Masculino , Camundongos , Camundongos Endogâmicos C57BLRESUMO
BACKGROUND AND PURPOSE: Chronic hypoperfusion in the mouse brain has been suggested to mimic aspects of vascular cognitive impairment, such as white matter damage. Although this model has attracted attention, our group has struggled to generate a reliable cognitive and pathological phenotype. This study aimed to identify neuroimaging biomarkers of brain pathology in aged, more severely hypoperfused mice. METHODS: We used magnetic resonance imaging to characterize brain degeneration in mice hypoperfused by refining the surgical procedure to use the smallest reported diameter microcoils (160 µm). RESULTS: Acute cerebral blood flow decreases were observed in the hypoperfused group that recovered over 1 month and coincided with arterial remodeling. Increasing hypoperfusion resulted in a reduction in spatial learning abilities in the water maze that has not been previously reported. We were unable to observe severe white matter damage with histology, but a novel approach to analyze diffusion tensor imaging data, graph theory, revealed substantial reorganization of the hypoperfused brain network. A logistic regression model from the data revealed that 3 network parameters were particularly efficient at predicting group membership (global and local efficiency and degrees), and clustering coefficient was correlated with performance in the water maze. CONCLUSIONS: Overall, these findings suggest that, despite the autoregulatory abilities of the mouse brain to compensate for a sudden decrease in blood flow, there is evidence of change in the brain networks that can be used as neuroimaging biomarkers to predict outcome.
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Encéfalo/diagnóstico por imagem , Circulação Cerebrovascular/fisiologia , Disfunção Cognitiva/diagnóstico por imagem , Modelos Animais de Doenças , Neuroimagem , Animais , Encéfalo/fisiologia , Disfunção Cognitiva/fisiopatologia , Masculino , Aprendizagem em Labirinto/fisiologia , Camundongos , Camundongos Endogâmicos C57BL , Vias Neurais/diagnóstico por imagem , Vias Neurais/fisiologia , Neuroimagem/métodos , Valor Preditivo dos TestesRESUMO
AIMS: Intracerebral hemorrhage (ICH) is a condition that arises due to the rupture of cerebral blood vessels, leading to the flow of blood into the brain tissue. One of the pathological alterations that occurs during an acute ICH is an impairment of the blood-brain barrier (BBB), which leads to severe perihematomal edema and an immune response. DISCUSSION: A complex interplay between the cells of the BBB, for example, pericytes, astrocytes, and brain endothelial cells, with resident and infiltrating immune cells, such as microglia, monocytes, neutrophils, T lymphocytes, and others accounts for both damaging and protective mechanisms at the BBB following ICH. However, the precise immunological influence of BBB disruption has yet to be richly ascertained, especially at various stages of ICH. CONCLUSION: This review summarizes the changes in different cell types and molecular components of the BBB associated with immune-inflammatory responses during ICH. Furthermore, it highlights promising immunoregulatory therapies to protect the integrity of the BBB after ICH. By offering a comprehensive understanding of the mechanisms behind BBB damage linked to cellular and molecular immunoinflammatory responses after ICH, this article aimed to accelerate the identification of potential therapeutic targets and expedite further translational research.
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Barreira Hematoencefálica , Hemorragia Cerebral , Humanos , Barreira Hematoencefálica/patologia , Barreira Hematoencefálica/imunologia , Hemorragia Cerebral/imunologia , Hemorragia Cerebral/patologia , Hemorragia Cerebral/metabolismo , AnimaisAssuntos
Isquemia Encefálica/terapia , Modelos Animais de Doenças , Transplante de Células-Tronco , Reabilitação do Acidente Vascular Cerebral , Acidente Vascular Cerebral/terapia , Animais , Isquemia Encefálica/patologia , Isquemia Encefálica/fisiopatologia , Imunomodulação , Camundongos , Neurogênese , Ratos , Regeneração , Acidente Vascular Cerebral/patologia , Acidente Vascular Cerebral/fisiopatologia , Acidente Vascular Cerebral Lacunar/patologia , Acidente Vascular Cerebral Lacunar/fisiopatologia , Acidente Vascular Cerebral Lacunar/terapia , Suínos , Substância Branca/patologiaRESUMO
Humans rely on vision as their most important sense. This is accomplished by photoreceptors (PRs) in the retina that detect light but cannot function without the support and maintenance of the retinal pigment epithelium (RPE). In subretinal hemorrhage (SRH), blood accumulates between the neurosensory retina and the RPE or between the RPE and the choroid. Blood breakdown products subsequently damage PRs and the RPE and lead to poor vision and blindness. Hence, there is a high need for options to preserve the retina and visual functions. We conducted a systematic review of the literature in accordance with the PRISMA guidelines to identify the cell death mechanisms in RPE and PRs after SRH to deepen our understanding of the pathways involved. After screening 736 publications published until November 8, 2022, we identified 19 records that assessed cell death in PRs and/or RPE in experimental models of SRH. Among the different cell death mechanisms, apoptosis was the most widely investigated mechanism (11 records), followed by ferroptosis (4), whereas necroptosis, pyroptosis, and lysosome-dependent cell death were only assessed in one study each. We discuss different therapeutic options that were assessed in these studies, including the removal of the hematoma/iron chelation, cytoprotection, anti-inflammatory agents, and antioxidants. Further systematic investigations will be necessary to determine the exact cell death mechanisms after SRH with respect to different blood breakdown components, cell types, and time courses. This will form the basis for the development of novel treatment options for SRH.
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Retina , Epitélio Pigmentado da Retina , Humanos , Epitélio Pigmentado da Retina/metabolismo , Morte Celular , Células Fotorreceptoras , HemorragiaRESUMO
Autofluorescence is frequently observed in animal tissues, interfering with an experimental analysis and leading to inaccurate results. Sudan black B (SBB) is a staining dye widely used in histological studies to eliminate autofluorescence. In this study, our objective was to characterize brain tissue autofluorescence present in three models of acute brain injury, including collagenase-induced intracerebral hemorrhage (ICH), traumatic brain injury (TBI), and middle cerebral artery occlusion, and to establish a simple method to block autofluorescence effectively. Using fluorescence microscopy, we examined autofluorescence in brain sections affected by ICH and TBI. In addition, we optimized a protocol to block autofluorescence with SBB pretreatment and evaluated the reduction in fluorescence intensity. Compared to untreated, pretreatment with SBB reduced brain tissue autofluorescence in the ICH model by 73.68% (FITC), 76.05% (Tx Red), and 71.88% (DAPI), respectively. In the TBI model, the ratio of pretreatment to untreated decreased by 56.85% (FITC), 44.28% (Tx Red), and 46.36% (DAPI), respectively. Furthermore, we tested the applicability of the protocol using immunofluorescence staining or Cyanine-5.5 labeling in the three models. SBB treatment is highly effective and can be applied to immunofluorescence and fluorescence label imaging techniques. SBB pretreatment effectively reduced background fluorescence but did not significantly reduce the specific fluorescence signal and greatly improved the signal-to-noise ratio of fluorescence imaging. In conclusion, the optimized SBB pretreatment protocol blocks brain section autofluorescence of the three acute brain injury models.
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Lesões Encefálicas Traumáticas , Lesões Encefálicas , Acidente Vascular Cerebral Hemorrágico , AVC Isquêmico , Animais , Fluoresceína-5-Isotiocianato , Encéfalo/diagnóstico por imagem , Hemorragia Cerebral/diagnóstico por imagemRESUMO
Acquired brain injuries, such as ischemic stroke, intracerebral hemorrhage (ICH), and traumatic brain injury (TBI), can cause severe neurologic damage and even death. Unfortunately, currently, there are no effective and safe treatments to reduce the high disability and mortality rates associated with these brain injuries. However, environmental enrichment (EE) is an emerging approach to treating and rehabilitating acquired brain injuries by promoting motor, sensory, and social stimulation. Multiple preclinical studies have shown that EE benefits functional recovery, including improved motor and cognitive function and psychological benefits mediated by complex protective signaling pathways. This article provides an overview of the enriched environment protocols used in animal models of ischemic stroke, ICH, and TBI, as well as relevant clinical studies, with a particular focus on ischemic stroke. Additionally, we explored studies of animals with stroke and TBI exposed to EE alone or in combination with multiple drugs and other rehabilitation modalities. Finally, we discuss the potential clinical applications of EE in future brain rehabilitation therapy and the molecular and cellular changes caused by EE in rodents with stroke or TBI. This article aims to advance preclinical and clinical research on EE rehabilitation therapy for acquired brain injury. © 2024 American Physiological Society. Compr Physiol 14:5291-5323, 2024.
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Lesões Encefálicas Traumáticas , Lesões Encefálicas , AVC Isquêmico , Acidente Vascular Cerebral , Ratos , Animais , Ratos Sprague-Dawley , Meio Ambiente , Lesões Encefálicas Traumáticas/terapia , Lesões Encefálicas Traumáticas/complicações , Lesões Encefálicas/complicações , Acidente Vascular Cerebral/terapia , Acidente Vascular Cerebral/complicações , AVC Isquêmico/complicações , Modelos Animais de DoençasRESUMO
The global trend toward aging populations has resulted in an increase in the occurrence of Alzheimer's disease (AD) and associated socioeconomic burdens. Abnormal metabolism of amyloid-ß (Aß) has been proposed as a significant pathomechanism in AD, supported by results of recent clinical trials using anti-Aß antibodies. Nonetheless, the cognitive benefits of the current treatments are limited. The etiology of AD is multifactorial, encompassing Aß and tau accumulation, neuroinflammation, demyelination, vascular dysfunction, and comorbidities, which collectively lead to widespread neurodegeneration in the brain and cognitive impairment. Hence, solely removing Aß from the brain may be insufficient to combat neurodegeneration and preserve cognition. To attain effective treatment for AD, it is necessary to (1) conduct extensive research on various mechanisms that cause neurodegeneration, including advances in neuroimaging techniques for earlier detection and a more precise characterization of molecular events at scales ranging from cellular to the full system level; (2) identify neuroprotective intervention targets against different neurodegeneration mechanisms; and (3) discover novel and optimal combinations of neuroprotective intervention strategies to maintain cognitive function in AD patients. The Alzheimer's Disease Neuroprotection Research Initiative's objective is to facilitate coordinated, multidisciplinary efforts to develop systemic neuroprotective strategies to combat AD. The aim is to achieve mitigation of the full spectrum of pathological processes underlying AD, with the goal of halting or even reversing cognitive decline.
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Intracerebral haemorrhage (ICH) is the second most common type of stroke and a major cause of mortality and disability worldwide. Despite advances in surgical interventions and acute ICH management, there is currently no effective therapy to improve functional outcomes in patients. Recently, there has been tremendous progress uncovering new pathophysiological mechanisms underlying ICH that may pave the way for the development of therapeutic interventions. Here, we highlight emerging targets, but also existing gaps in preclinical animal modelling that prevent their exploitation. We particularly focus on (1) ICH aetiology, (2) the haematoma, (3) inflammation, and (4) post-ICH pathology. It is important to recognize that beyond neurons and the brain, other cell types and organs are crucially involved in ICH pathophysiology and successful interventions likely will need to address the entire organism. This review will spur the development of successful therapeutic interventions for ICH and advanced animal models that better reflect its aetiology and pathophysiology.
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Hemorragia Cerebral , Acidente Vascular Cerebral , Animais , Encéfalo/patologia , Hemorragia Cerebral/etiologia , Hemorragia Cerebral/patologia , Hemorragia Cerebral/terapia , Hematoma/etiologia , Hematoma/patologia , Hematoma/terapia , Humanos , Inflamação/patologia , Acidente Vascular Cerebral/patologiaRESUMO
Neural stem cell (NSC) transplantation is an emerging and promising approach to combat neurodegenerative diseases. While NSCs can differentiate into neural cell types, many therapeutic effects are mediated by paracrine, "drug-like" mechanisms. Neurodegenerative diseases are predominantly a burden of the elderly who commonly suffer from comorbidities and thus are subject to pharmacotherapies. There is substantial knowledge about drug-drug interactions but almost nothing is known about a potential impact of pharmacotherapy on NSCs. Such knowledge is decisive for designing tailored treatment programs for individual patients. Previous studies revealed preliminary evidence that the anti-depressants fluoxetine and imipramine may affect NSC viability and proliferation. Here, we derive a hypothesis on how commonly applied drugs, statins and antihypertensives, may affect NSC viability, proliferation, and differentiation. We conducted a systematic review and meta-analysis looking at potential effects of commonly prescribed antihypertensive and antihyperlipidemic medication on NSC function. PubMed and Web of Science databases were searched on according to the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guidelines. Publications were assessed against a priori established selection criteria for relevancy. A meta-analysis was then performed on data extracted from publications eligible for full text review to estimate drug effects on NSC functions. Our systematic review identified 1,017 potential studies, 55 of which were eligible for full text review. Out of those, 21 were included in the qualitative synthesis. The meta-analysis was performed on 13 publications; the remainder were excluded as they met exclusion criteria or lacked sufficient data to perform a meta-analysis. The meta-analysis revealed that alpha-2 adrenoceptor agonists, an anti-hypertensive drug class [p < 0.05, 95% confidence intervals (CI) = -1.54; -0.35], and various statins [p < 0.05, 95% CI = -3.17; -0.0694] had an inhibiting effect on NSC proliferation. Moreover, we present preliminary evidence that L-type calcium channel blockers and statins, particularly lovastatin, may reduce NSC viability. Although the data available in the literature is limited, there are clear indications for an impact of commonly applied drugs, in particular statins, on NSC function. Considering the modes of action of the respective drugs, we reveal plausible mechanisms by which this impact may be mediated, creating a testable hypothesis, and providing insights into how future confirmative research on this topic may be conducted.
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Axonal degeneration (AxD) is a pathological hallmark of many neurodegenerative diseases. Deciphering the morphological patterns of AxD will help to understand the underlying mechanisms and develop effective therapies. Here, we evaluated the progression of AxD in cortical neurons using a novel microfluidic device together with a deep learning tool that we developed for the enhanced-throughput analysis of AxD on microscopic images. The trained convolutional neural network (CNN) sensitively and specifically segmented the features of AxD including axons, axonal swellings, and axonal fragments. Its performance exceeded that of the human evaluators. In an in vitro model of AxD in hemorrhagic stroke induced by the hemolysis product hemin, we detected a time-dependent degeneration of axons leading to a decrease in axon area, while axonal swelling and fragment areas increased. Axonal swellings preceded axon fragmentation, suggesting that swellings may be reliable predictors of AxD. Using a recurrent neural network (RNN), we identified four morphological patterns of AxD (granular, retraction, swelling, and transport degeneration). These findings indicate a morphological heterogeneity of AxD in hemorrhagic stroke. Our EntireAxon platform enables the systematic analysis of axons and AxD in time-lapse microscopy and unravels a so-far unknown intricacy in which AxD can occur in a disease context.
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Axônios/patologia , Aprendizado Profundo , Degeneração Neural/patologia , Neurônios/patologia , Animais , Morte Celular/efeitos dos fármacos , Modelos Animais de Doenças , Humanos , Doenças Neurodegenerativas/patologiaRESUMO
Coronavirus disease 2019 (COVID-19) can damage cerebral small vessels and cause neurological symptoms. Here we describe structural changes in cerebral small vessels of patients with COVID-19 and elucidate potential mechanisms underlying the vascular pathology. In brains of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-infected individuals and animal models, we found an increased number of empty basement membrane tubes, so-called string vessels representing remnants of lost capillaries. We obtained evidence that brain endothelial cells are infected and that the main protease of SARS-CoV-2 (Mpro) cleaves NEMO, the essential modulator of nuclear factor-κB. By ablating NEMO, Mpro induces the death of human brain endothelial cells and the occurrence of string vessels in mice. Deletion of receptor-interacting protein kinase (RIPK) 3, a mediator of regulated cell death, blocks the vessel rarefaction and disruption of the blood-brain barrier due to NEMO ablation. Importantly, a pharmacological inhibitor of RIPK signaling prevented the Mpro-induced microvascular pathology. Our data suggest RIPK as a potential therapeutic target to treat the neuropathology of COVID-19.
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Barreira Hematoencefálica/metabolismo , Encéfalo/metabolismo , Proteases 3C de Coronavírus/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Microvasos/metabolismo , SARS-CoV-2/metabolismo , Animais , Barreira Hematoencefálica/patologia , Encéfalo/patologia , Chlorocebus aethiops , Proteases 3C de Coronavírus/genética , Cricetinae , Feminino , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/genética , Masculino , Mesocricetus , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Microvasos/patologia , SARS-CoV-2/genética , Células VeroRESUMO
Stem cell therapy is a promising treatment option for neurodegenerative diseases that mostly affect geriatric patients who often suffer from comorbidities requiring multiple medications. However, not much is known about the interactions between stem cells and drugs. Here, we focus on the potential interactions between drugs used to treat the comorbidities or sequelae of neurodegenerative diseases and neuronal stem cells to reveal potential effects on drug safety and efficacy. To determine the potential effects of drugs frequently used in geriatric patients (analgesic, antibiotic, antidepressant, antidiabetic, antihyperlipidemic, and antihypertensive drugs) on neuronal stem cell differentiation and proliferation, we systematically searched PubMed to identify nonreview articles published in English in peer-reviewed journals between January 1, 1991, and June 7, 2018. We identified 5,954 publications, of which 214 were included. Only 62 publications provided the complete data sets required for meta-analysis. We found that antidepressants stimulated neuronal stem cell proliferation but not differentiation under physiologic conditions and increased the proliferation of stem cells in the context of stress. Several other potential interactions were identified, but the limited number of available data sets precludes robust conclusions. Although available data were in most cases insufficient to perform robust meta-analysis, a clear interaction between antidepressants and neuronal stem cells was identified. We reveal other potential interactions requiring further experimental investigation. We recommend that future research addresses such interactions and investigates the best combination of pharmacological interventions and neuronal stem cell treatments for more efficient and safer patient care. Stem Cells Translational Medicine 2019;8:1202-1211.
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Antidepressivos/farmacologia , Diferenciação Celular , Proliferação de Células , Interações Medicamentosas , Células-Tronco Neurais/patologia , Humanos , Células-Tronco Neurais/efeitos dos fármacosRESUMO
The supply of oxygen and nutrients to the brain is vital for its function and requires a complex vascular network that, when disturbed, results in profound neurological dysfunction. As part of the pathology in stroke, endothelial cells die. As endothelial cell death affects the surrounding cellular environment and is a potential target for the treatment and prevention of neurological disorders, we have systematically reviewed important aspects of endothelial cell death with a particular focus on stroke. After screening 2876 publications published between January 1, 2010 and August 7, 2019, we identified 154 records to be included. We found that endothelial cell death occurs rapidly as well as later after the onset of stroke conditions. Among the different cell death mechanisms, apoptosis was the most widely investigated (92 records), followed by autophagy (20 records), while other, more recently defined mechanisms received less attention, such as lysosome-dependent cell death (2 records) and necroptosis (2 records). We also discuss the differential vulnerability of brain cells to injury after stroke and the role of endothelial cell death in the no-reflow phenomenon with a special focus on the microvasculature. Further investigation of the different cell death mechanisms using novel tools and biomarkers will greatly enhance our understanding of endothelial cell death. For this task, at least two markers/criteria are desirable to determine cell death subroutines according to the recommendations of the Nomenclature Committee on Cell Death.