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1.
Biomacromolecules ; 25(8): 4879-4890, 2024 Aug 12.
Artigo em Inglês | MEDLINE | ID: mdl-39001820

RESUMO

Cerebral aneurysms are a source of neurological morbidity and mortality, most often as a result of rupture. The most common approach for treating aneurysms involves endovascular embolization using nonbiodegradable medical devices, such as platinum coils. However, the need for retreatment due to the recanalization of coil-treated aneurysms highlights the importance of exploring alternative solutions. In this study, we propose an injectable extracellular matrix-derived embolic formed in situ by Michael addition of gelatin-thiol (Gel-SH) and hyaluronic acid vinyl sulfone (HA-VS) that may be delivered with a therapeutic agent (here, RADA-SP) to fill and remodel aneurysmal tissue without leaving behind permanent foreign bodies. The injectable embolic material demonstrated rapid gelation under physiological conditions, forming a highly porous structure and allowing for cellular infiltration. The injectable embolic exhibited thrombogenic behavior in vitro that was comparable to that of alginate injectables. Furthermore, in vivo studies in a murine carotid aneurysm model demonstrated the successful embolization of a saccular aneurysm and extensive cellular infiltration both with and without RADA-SP at 3 weeks, with some evidence of increased vascular or fibrosis markers with RADA-SP incorporation. The results indicate that the developed embolic has inherent potential for acutely filling cerebrovascular aneurysms and encouraging the cellular infiltration that would be necessary for stable, chronic remodeling.


Assuntos
Embolização Terapêutica , Matriz Extracelular , Aneurisma Intracraniano , Animais , Aneurisma Intracraniano/terapia , Embolização Terapêutica/métodos , Camundongos , Ácido Hialurônico/química , Gelatina/química , Masculino , Humanos
2.
Childs Nerv Syst ; 40(7): 2033-2042, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38649470

RESUMO

Pediatric optic pathway/hypothalamic gliomas (OPHG) pose challenges in treatment due to their location and proximity to vital structures. Surgical resection plays a key role in the management of OPHG especially when the tumor exhibits mass effect and causes symptoms. However, data regarding outcomes and complications of surgical resection for OPHG remains heterogenous. The authors performed a systematic review on pediatric OPHG in four databases: PubMed, EMBASE, Cochrane Library, and Google Scholar. We included studies that reported on the visual outcomes and complications of OPHG resection. A meta-analysis was performed and reported per the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. A total of 26 retrospective studies were included. Seven hundred ninety-seven pediatric patients with OPHG undergoing surgical resection were examined. A diagnosis of NF1 was confirmed in 9.7%. Gross total resection was achieved in 36.7%. Intraorbital optic pathway gliomas showed a significantly higher gross total resection rate compared to those located in the chiasmatic/hypothalamic region (75.8% vs. 9.6%). Postoperatively, visual acuity improved in 24.6%, remained unchanged in 68.2%, and worsened in 18.2%. Complications included hydrocephalus (35.4%), anterior pituitary dysfunction (19.6%), and transient diabetes insipidus (29%). Tumor progression post-resection occurred in 12.8%, through a mean follow-up of 53.5 months. Surgical resection remains an essential strategy for treating symptomatic and large pediatric OPHG and can result in favorable vision outcomes in most patients. Careful patient selection is critical. Patients should be monitored for hydrocephalus development postoperatively and followed up to assess for tumor progression and adjuvant treatment necessity.


Assuntos
Neoplasias Hipotalâmicas , Complicações Pós-Operatórias , Humanos , Criança , Complicações Pós-Operatórias/etiologia , Complicações Pós-Operatórias/epidemiologia , Neoplasias Hipotalâmicas/cirurgia , Neoplasias Hipotalâmicas/complicações , Glioma/cirurgia , Glioma/complicações , Glioma do Nervo Óptico/cirurgia , Procedimentos Neurocirúrgicos/métodos , Procedimentos Neurocirúrgicos/efeitos adversos , Resultado do Tratamento , Pré-Escolar
3.
Cell Mol Neurobiol ; 43(6): 2697-2711, 2023 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-37046105

RESUMO

Intracranial aneurysms are reported to affect 2-5% of the population. Despite advances in the surgical management of this disease, diagnostic technologies have marginally improved and still rely on expensive or invasive imaging procedures. Currently, there is no blood-based test to detect cerebral aneurysm formation or quantify the risk of rupture. The aim of this review is to summarize current literature on the mechanism of aneurysm formation, specifically studies relating to inflammation, and provide a rationale and commentary on a hypothetical future blood-based test. Efforts should be focused on clinical-translational approaches to create an assay to screen for cerebral aneurysm presence and risk-stratify patients to allow for superior treatment timing and management. Cerebral Aneurysm Blood Test Considerations: There are multiple caveats to development of a putative blood test to detect cerebral aneurysm presence.


Assuntos
Aneurisma Intracraniano , Humanos , Aneurisma Intracraniano/diagnóstico , Proteômica , Inflamação
4.
J Pineal Res ; 75(4): e12909, 2023 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-37721126

RESUMO

Huntington's disease (HD) is a progressive neurodegenerative brain disorder associated with uncontrolled body movements, cognitive decline, and reduced circulating melatonin levels. Melatonin is a potent antioxidant and exogenous melatonin treatment is neuroprotective in experimental HD models. In neurons, melatonin is exclusively synthesized in the mitochondrial matrix. Thus, we investigated the integrity of melatonin biosynthesis pathways in pineal and extrapineal brain areas in human HD brain samples, in the R6/2 mouse model of HD and in full-length mutant huntingtin knock-in cells. Aralkylamine N-acetyltransferase (AANAT) is the rate-limiting step enzyme in the melatonin biosynthetic pathway. We found that AANAT expression is significantly decreased in the pineal gland and the striatum of HD patients compared to normal controls. In the R6/2 mouse forebrain, AANAT protein expression was decreased in synaptosomal, but not nonsynaptosomal, mitochondria and was associated with decreased synaptosomal melatonin levels compared to wild type mice. We also demonstrate sequestration of AANAT in mutant-huntingtin protein aggregates likely resulting in decreased AANAT bioavailability. Paradoxically, AANAT mRNA expression is increased in tissues where AANAT protein expression is decreased, suggesting a potential feedback loop that is, ultimately unsuccessful. In conclusion, we demonstrate that pineal, extrapineal, and synaptosomal melatonin levels are compromised in the brains of HD patients and R6/2 mice due, at least in part, to protein aggregation.


Assuntos
Doença de Huntington , Melatonina , Glândula Pineal , Humanos , Camundongos , Animais , Melatonina/metabolismo , Glândula Pineal/metabolismo
5.
Neurosurg Focus ; 54(5): E9, 2023 05.
Artigo em Inglês | MEDLINE | ID: mdl-37127027

RESUMO

OBJECTIVE: The aim of this study was to describe the efficacy, clinical outcomes, and complications of open cerebrovascular surgery, endovascular surgery, and conservative management of dolichoectatic vertebrobasilar aneurysms (DVBAs). METHODS: Relevant articles were retrieved from PubMed, Scopus, Web of Science, and Cochrane databases according to PRISMA guidelines. A meta-analysis was conducted for clinical presentation, treatment protocols, and clinical outcomes-good (improved or stable clinical status) or poor (deteriorated clinical status or death)-and mortality rates. RESULTS: The 9 identified articles described 41 cases (27.5%) of open cerebrovascular surgery, 61 endovascular procedures (40.9%), and 47 cases (31.5%) of conservative management for DVBAs. The total cohort had a good outcome rate of 51.9% (95% CI 28.3%-74.6%), a poor outcome rate of 45.5% (95% CI 23.0%-70.1%), and a mortality rate of 22.3% (95% CI 11.8%-38.0%). The treatment groups had comparable good clinical outcome rates (open cerebrovascular surgery group: 24.7% [95% CI 2.9%-78.2%]; endovascular surgery group: 69.0% [95% CI 28.7%-92.5%]; conservative management group: 57.7% [95% CI 13.0%-92.5%]; p = 0.19) and poor outcome rates (open vascular surgery group: 75.3% [95% CI 21.8%-97.1%]; endovascular surgery group: 27.2% [95% CI 5.6%-0.70.2%]; conservative management group: 39.9% [95% CI 9.1%-81.6%]; p = 0.15). The treatment groups also had comparable mortality rates (open vascular surgery group: 39.5% [95% CI 11.4%-76.8%]; endovascular surgery group: 15.8% [95% CI 4.4%-43.0%]; conservative management group: 19.2% [95% CI 6.8%-43.5%]; p = 0.23). CONCLUSIONS: The current study of DVBAs illustrated poor outcomes and high mortality rates regardless of the treatment modality. The subgroup analysis showed heterogeneity among the subgroups and advice for personalized management.


Assuntos
Procedimentos Endovasculares , Aneurisma Intracraniano , Humanos , Aneurisma Intracraniano/cirurgia , Resultado do Tratamento , Procedimentos Endovasculares/métodos
8.
Proc Natl Acad Sci U S A ; 116(33): 16593-16602, 2019 08 13.
Artigo em Inglês | MEDLINE | ID: mdl-31346086

RESUMO

Mutant huntingtin (mHTT), the causative protein in Huntington's disease (HD), associates with the translocase of mitochondrial inner membrane 23 (TIM23) complex, resulting in inhibition of synaptic mitochondrial protein import first detected in presymptomatic HD mice. The early timing of this event suggests that it is a relevant and direct pathophysiologic consequence of mHTT expression. We show that, of the 4 TIM23 complex proteins, mHTT specifically binds to the TIM23 subunit and that full-length wild-type huntingtin (wtHTT) and mHTT reside in the mitochondrial intermembrane space. We investigated differences in mitochondrial proteome between wtHTT and mHTT cells and found numerous proteomic disparities between mHTT and wtHTT mitochondria. We validated these data by quantitative immunoblotting in striatal cell lines and human HD brain tissue. The level of soluble matrix mitochondrial proteins imported through the TIM23 complex is lower in mHTT-expressing cell lines and brain tissues of HD patients compared with controls. In mHTT-expressing cell lines, membrane-bound TIM23-imported proteins have lower intramitochondrial levels, whereas inner membrane multispan proteins that are imported via the TIM22 pathway and proteins integrated into the outer membrane generally remain unchanged. In summary, we show that, in mitochondria, huntingtin is located in the intermembrane space, that mHTT binds with high-affinity to TIM23, and that mitochondria from mHTT-expressing cells and brain tissues of HD patients have reduced levels of nuclearly encoded proteins imported through TIM23. These data demonstrate the mechanism and biological significance of mHTT-mediated inhibition of mitochondrial protein import, a mechanism likely broadly relevant to other neurodegenerative diseases.


Assuntos
Proteína Huntingtina/metabolismo , Mitocôndrias/metabolismo , Proteínas de Transporte da Membrana Mitocondrial/metabolismo , Proteínas Mutantes/metabolismo , Proteostase , Linhagem Celular , Núcleo Celular/metabolismo , Córtex Cerebral/patologia , Corpo Estriado/patologia , Humanos , Doença de Huntington , Membranas Mitocondriais/metabolismo , Proteínas do Complexo de Importação de Proteína Precursora Mitocondrial , Proteínas Mitocondriais/metabolismo , Ligação Proteica , Proteoma/metabolismo
9.
Proc Natl Acad Sci U S A ; 116(2): 650-659, 2019 01 08.
Artigo em Inglês | MEDLINE | ID: mdl-30584104

RESUMO

Neuritic retraction in the absence of overt neuronal death is a shared feature of normal aging and neurodegenerative disorders, but the intracellular mechanisms modulating this process are not understood. We propose that cumulative distal mitochondrial protein damage results in impaired protein import, leading to mitochondrial dysfunction and focal activation of the canonical apoptosis pathway in neurites. This is a controlled process that may not lead to neuronal death and, thus, we term this phenomenon "neuritosis." Consistent with our hypothesis, we show that in primary cerebrocortical neurons, mitochondrial distance from the soma correlates with increased mitochondrial protein damage, PINK1 accumulation, reactive oxygen species production, and decreased mitochondrial membrane potential and depolarization threshold. Furthermore, we demonstrate that the distance-dependent mitochondrial membrane potential gradient exists in vivo in mice. We demonstrate that impaired distal mitochondria have a lower threshold for focal/nonlethal neuritic caspase-3 activation in normal neurons that is exacerbated in aging, stress, and neurodegenerative conditions, thus delineating a fundamental mechanistic underpinning for synaptic vulnerability.


Assuntos
Apoptose , Potencial da Membrana Mitocondrial , Mitocôndrias/metabolismo , Neuritos/metabolismo , Doenças Neurodegenerativas/metabolismo , Animais , Caspase 3/genética , Caspase 3/metabolismo , Camundongos , Camundongos Transgênicos , Mitocôndrias/genética , Mitocôndrias/patologia , Neuritos/patologia , Doenças Neurodegenerativas/genética , Doenças Neurodegenerativas/patologia , Proteínas Quinases/genética , Proteínas Quinases/metabolismo , Espécies Reativas de Oxigênio/metabolismo
10.
Neurobiol Dis ; 158: 105451, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34298088

RESUMO

In healthy neurons, a mitochondrial membrane potential gradient exists whereby membrane potential is highest in the soma and decreases with distance from the nucleus. Correspondingly, distal mitochondria have more oxidative damage and slower protein import than somal mitochondria. Due to these differences, distal mitochondria have an intrinsic first stressor that somal mitochondria do not have, resulting in synaptic mitochondrial vulnerability. A second stressor may result from mutant protein expression, situational stress, or aging, exacerbating vulnerable mitochondria activating stress responses. Under these conditions, distal mitochondria release cytochrome c and mitochondrial DNA, leading to compartmentalized sub-lethal caspase-3 activation and cytokine production. In this two-hit mitochondrial-driven synaptic loss model, synapse vulnerability during neurodegeneration is explained as a superposition of pre-existing lower synaptic mitochondrial membrane potential (hit one) with additional mitochondrial stress (hit two). This two-hit mechanism occurs in synaptic mitochondria, activating signaling pathways leading to synaptic degeneration, as a potential preamble to neuronal death.


Assuntos
Mitocôndrias/patologia , Doenças Neurodegenerativas/patologia , Sinapses/patologia , Animais , Modelos Animais de Doenças , Humanos , Potencial da Membrana Mitocondrial , Estresse Oxidativo
11.
Proc Natl Acad Sci U S A ; 114(38): E7997-E8006, 2017 09 19.
Artigo em Inglês | MEDLINE | ID: mdl-28874589

RESUMO

G protein-coupled receptors (GPCRs) are classically characterized as cell-surface receptors transmitting extracellular signals into cells. Here we show that central components of a GPCR signaling system comprised of the melatonin type 1 receptor (MT1), its associated G protein, and ß-arrestins are on and within neuronal mitochondria. We discovered that the ligand melatonin is exclusively synthesized in the mitochondrial matrix and released by the organelle activating the mitochondrial MT1 signal-transduction pathway inhibiting stress-mediated cytochrome c release and caspase activation. These findings coupled with our observation that mitochondrial MT1 overexpression reduces ischemic brain injury in mice delineate a mitochondrial GPCR mechanism contributing to the neuroprotective action of melatonin. We propose a new term, "automitocrine," analogous to "autocrine" when a similar phenomenon occurs at the cellular level, to describe this unexpected intracellular organelle ligand-receptor pathway that opens a new research avenue investigating mitochondrial GPCR biology.


Assuntos
Lesões Encefálicas/metabolismo , Isquemia Encefálica/metabolismo , Melatonina/biossíntese , Mitocôndrias/metabolismo , Receptor MT1 de Melatonina/metabolismo , Transdução de Sinais , Animais , Lesões Encefálicas/genética , Isquemia Encefálica/genética , Citocromos c/genética , Citocromos c/metabolismo , Masculino , Melatonina/genética , Camundongos , Mitocôndrias/genética , Receptor MT1 de Melatonina/genética
12.
J Mol Cell Cardiol ; 126: 50-59, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30448480

RESUMO

Inflammation is critical in the pathobiology of atherosclerosis. An essential player in the inflammatory process in atherosclerosis are macrophages that scavenge oxidatively modified low-density lipoproteins (OxLDL) deposited in the subendothelium of systemic arteries that secrete a myriad of pro-inflammatory mediators. Here, we identified that a subunit of the Skp-Cullin-F-box ubiquitin E3 ligase apparatus, termed FBXO3, modulates the inflammatory response in atherosclerosis. Specifically, individuals with a hypofunctioning genetic variant of FBXO3 develop less atherosclerosis. FBXO3 protein is present in cells of monocytic lineage within carotid plaques and its levels increase in those with symptomatic compared with asymptomatic atherosclerosis. Further, cellular depletion or small molecule inhibition of FBXO3 significantly reduced the inflammatory response to OxLDL by macrophages without altering OxLDL uptake. Thus, FBXO3 potentiates vascular inflammation and atherosclerosis that can be effectively mitigated by a small molecule inhibitor.


Assuntos
Aterosclerose/enzimologia , Inflamação/enzimologia , Ubiquitina-Proteína Ligases/metabolismo , Adulto , Idoso , Artérias Carótidas/efeitos dos fármacos , Artérias Carótidas/patologia , Vasos Coronários/efeitos dos fármacos , Vasos Coronários/patologia , Endocitose/efeitos dos fármacos , Inibidores Enzimáticos/farmacologia , Proteínas F-Box/genética , Feminino , Variação Genética , Humanos , Lipoproteínas LDL/metabolismo , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Masculino , Pessoa de Meia-Idade , Bibliotecas de Moléculas Pequenas/farmacologia , Células THP-1
13.
JAMA ; 321(13): 1295-1303, 2019 Apr 02.
Artigo em Inglês | MEDLINE | ID: mdl-30938800

RESUMO

IMPORTANCE: Although spontaneous intraparenchymal hemorrhage (IPH) accounts for less than 20% of cases of stroke, it continues to be associated with the highest mortality of all forms of stroke and substantial morbidity rates. OBSERVATIONS: Early identification and management of IPH is crucial. Blood pressure control, reversal of associated coagulopathy, care in a dedicated stroke unit, and identification of secondary etiologies are essential to optimizing outcomes. Surgical management of hydrocephalus and space occupying hemorrhage in the posterior fossa are accepted forms of treatment. Modern advances in minimally invasive surgical management of primary, supratentorial IPH are being explored in randomized trials. Hemorrhagic arteriovenous malformations and cavernous malformations are surgically excised if accessible, while hemorrhagic dural arteriovenous fistulas and distal/mycotic aneurysms are often managed with embolization if feasible. CONCLUSIONS AND RELEVANCE: IPH remains a considerable source of neurological morbidity and mortality. Rapid identification, medical management, and neurosurgical management, when indicated, are essential to facilitate recovery. There is ongoing evaluation of minimally invasive approaches for evacuation of primary IPH and evolution of surgical and endovascular techniques in the management of lesions leading to secondary IPH.


Assuntos
Hemorragia Cerebral/terapia , Procedimentos Cirúrgicos Minimamente Invasivos , Malformações Arteriovenosas/complicações , Malformações Arteriovenosas/cirurgia , Hemorragia Cerebral/diagnóstico , Hemorragia Cerebral/etiologia , Hemorragia Cerebral/reabilitação , Técnicas Hemostáticas , Humanos , Hipertensão/complicações , Hipertensão/tratamento farmacológico , Acidente Vascular Cerebral
14.
J Pineal Res ; 64(1)2018 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-28796402

RESUMO

The function of melatonin as a protective agent against newborn hypoxic-ischemic (H-I) brain injury is not yet well studied, and the mechanisms by which melatonin causes neuroprotection in neurological diseases are still evolving. This study was designed to investigate whether expression of MT1 receptors is reduced in newborn H-I brain injury and whether the protective action of melatonin is by alterations of the MT1 receptors. We demonstrated that there was significant reduction in MT1 receptors in ischemic brain of mouse pups in vivo following H-I brain injury and that melatonin offers neuroprotection through upregulation of MT1 receptors. The role of MT1 receptors was further supported by observation of increased mortality in MT1 knockout mice following H-I brain injury and the reversal of the inhibitory role of melatonin on mitochondrial cell death pathways by the melatonin receptor antagonist, luzindole. These data demonstrate that melatonin mediates its neuroprotective effect in mouse models of newborn H-I brain injury, at least in part, by the restoration of MT1 receptors, the inhibition of mitochondrial cell death pathways and the suppression of astrocytic and microglial activation.


Assuntos
Hipóxia-Isquemia Encefálica/tratamento farmacológico , Hipóxia-Isquemia Encefálica/metabolismo , Melatonina/uso terapêutico , Receptor MT1 de Melatonina/metabolismo , Animais , Astrócitos/citologia , Western Blotting , Células Cultivadas , Feminino , Genótipo , Hipocampo/citologia , Imuno-Histoquímica , Masculino , Potenciais da Membrana/fisiologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Modelos Teóricos , Receptor MT1 de Melatonina/genética
15.
Neurobiol Dis ; 105: 156-163, 2017 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-28461247

RESUMO

Modulation of miRNA expression has been shown to be beneficial in the context of multiple diseases. The purpose of this study was to determine if an inhibitor of miR-337-3p is neuroprotective for hypoxic injury after tail vein injection. We evaluated miR-337-3p expression levels and in brain tissue in vivo before and after permanent middle cerebral artery occlusion (pMCAO) in mice. Subsequently, a custom locked nucleic acid (LNA) antimir-337-3p oligonucleotide was developed and tested in vitro after induction of oxygen glucose-deprivation (OGD) and in vivo by injection into the mouse tail vein for 3 consecutive days before pMCAO. Ischemic lesion volume was measured by TTC staining. We show that systemically administered LNA antimir-337-3p crosses the blood brain-brain-barrier (BBB), penetrates into neurosn, downregulates endogenous miR-337-3p expression and reduces ischemic brain injury. The findings support the use of similar antimir-LNA constructs as novel therapies in neurological disease.


Assuntos
Anticorpos/administração & dosagem , Lesões Encefálicas/tratamento farmacológico , Lesões Encefálicas/etiologia , Infarto da Artéria Cerebral Média/complicações , MicroRNAs/metabolismo , Análise de Variância , Animais , Pressão Sanguínea/efeitos dos fármacos , Caspases/metabolismo , Morte Celular/efeitos dos fármacos , Morte Celular/genética , Células Cultivadas , Córtex Cerebral/citologia , Modelos Animais de Doenças , Glucose/deficiência , Hipóxia/tratamento farmacológico , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Exame Neurológico , Neurônios/efeitos dos fármacos , Oligonucleotídeos/uso terapêutico , Fatores de Tempo
17.
Acta Neurochir (Wien) ; 158(12): 2377-2383, 2016 12.
Artigo em Inglês | MEDLINE | ID: mdl-27696001

RESUMO

BACKGROUND: Carotid endarterectomy (CEA) is the procedure of choice for reducing the risk of stroke in both symptomatic and asymptomatic carotid artery stenoses. Stroke is associated with significant morbidity and mortality peri-operatively (2-3 %). Our primary aim is to evaluate the etiology of these strokes after CEA and their impact on morbidity by comparing the length of stay in the hospital. METHODS: A total of 584 patients with documented neurological status evaluations who underwent CEAs were included in the study. Neurophysiological monitoring data was obtained during CEA for carotid stenosis included eight-channel electroencephalography (EEG) and upper extremity somatosensory evoked potentials (SSEPs). RESULTS: Twenty-one (3.595 %) patients had strokes in the perioperative period and they were more likely to have left-sided surgery (p = 0.008), intraoperative monitoring (IOM) changes (p < 0.001), an intraoperative shunt placed (p = 0.0002) or a hospital stay longer than 5 days (p = 0.0042). Unilateral anterior circulation ischemic stroke were the most common in our series. In a logistic regression model, left-sided surgery was shown to be 4.78 times more likely to be associated with perioperative stroke (1.50-15.27; p = 0.008) while intraoperative shunts were 11.85 times more likely to have strokes (3.97-35.34; p < 0.0001). Patients with stenosis greater than 70 % were 6.67 times less likely to have a stroke (0.04-0.59; p = 0.007). CONCLUSIONS: Ischemic anterior circulation strokes are the most common type of post-operative neurological changes in patients undergoing CEA. Intraoperative shunt placement was a strong predictor of perioperative strokes. Since shunts are only placed following intraoperative monitoring changes, SSEPs and EEG can therefore function as a biomarker of cerebral hypo-perfusion.


Assuntos
Estenose das Carótidas/cirurgia , Endarterectomia das Carótidas/efeitos adversos , Complicações Pós-Operatórias/etiologia , Acidente Vascular Cerebral/etiologia , Idoso , Eletroencefalografia , Potenciais Somatossensoriais Evocados , Feminino , Humanos , Monitorização Neurofisiológica Intraoperatória , Masculino , Pessoa de Meia-Idade , Complicações Pós-Operatórias/prevenção & controle , Acidente Vascular Cerebral/prevenção & controle
18.
J Neurosci ; 34(8): 2967-78, 2014 Feb 19.
Artigo em Inglês | MEDLINE | ID: mdl-24553937

RESUMO

N-acetylserotonin (NAS) is an immediate precursor of melatonin, which we have reported is neuroprotective against ischemic injury. Here we test whether NAS is a potential neuroprotective agent in experimental models of ischemic injury. We demonstrate that NAS inhibits cell death induced by oxygen-glucose deprivation or H2O2 in primary cerebrocortical neurons and primary hippocampal neurons in vitro, and organotypic hippocampal slice cultures ex vivo and reduces hypoxia/ischemia injury in the middle cerebral artery occlusion mouse model of cerebral ischemia in vivo. We find that NAS is neuroprotective by inhibiting the mitochondrial cell death pathway and the autophagic cell death pathway. The neuroprotective effects of NAS may result from the influence of mitochondrial permeability transition pore opening, mitochondrial fragmentation, and inhibition of the subsequent release of apoptogenic factors cytochrome c, Smac, and apoptosis-inducing factor from mitochondria to cytoplasm, and activation of caspase-3, -9, as well as the suppression of the activation of autophagy under stress conditions by increasing LC3-II and Beclin-1 levels and decreasing p62 level. However, NAS, unlike melatonin, does not provide neuroprotection through the activation of melatonin receptor 1A. We demonstrate that NAS reaches the brain subsequent to intraperitoneal injection using liquid chromatography/mass spectrometry analysis. Given that it occurs naturally and has low toxicity, NAS, like melatonin, has potential as a novel therapy for ischemic injury.


Assuntos
Autofagia/efeitos dos fármacos , Isquemia Encefálica/patologia , Morte Celular/efeitos dos fármacos , Mitocôndrias/efeitos dos fármacos , Fármacos Neuroprotetores , Serotonina/análogos & derivados , Animais , Apoptose/efeitos dos fármacos , Proteínas Reguladoras de Apoptose/genética , Proteínas Reguladoras de Apoptose/fisiologia , Células Cultivadas , Córtex Cerebral/citologia , Córtex Cerebral/patologia , Hipocampo/citologia , Hipocampo/patologia , Peróxido de Hidrogênio/toxicidade , Imuno-Histoquímica , Infarto da Artéria Cerebral Média/patologia , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos C57BL , Permeabilidade , Serotonina/metabolismo , Serotonina/farmacologia , Transdução de Sinais/efeitos dos fármacos , Frações Subcelulares/efeitos dos fármacos
19.
Biochim Biophys Acta ; 1842(11): 2286-2297, 2014 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-25127851

RESUMO

Diffusion MRI enabled in vivo microstructural imaging of the fiber tracts in the brain resulting in its application in a wide range of settings, including in neurological and neurosurgical disorders. Conventional approaches such as diffusion tensor imaging (DTI) have been shown to have limited applications due to the crossing fiber problem and the susceptibility of their quantitative indices to partial volume effects. To overcome these limitations, the recent focus has shifted to the advanced acquisition methods and their related analytical approaches. Advanced white matter imaging techniques provide superior qualitative data in terms of demonstration of multiple crossing fibers in their spatial orientation in a three dimensional manner in the brain. In this review paper, we discuss the advancements in diffusion MRI and introduce their roles. Using examples, we demonstrate the role of advanced diffusion MRI-based fiber tracking in neuroanatomical studies. Results from its preliminary application in the evaluation of intracranial space occupying lesions, including with respect to future directions for prognostication, are also presented. Building upon the previous DTI studies assessing white matter disease in Huntington's disease and Amyotrophic lateral sclerosis; we also discuss approaches which have led to encouraging preliminary results towards developing an imaging biomarker for these conditions.

20.
Stroke ; 46(12): 3514-22, 2015 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-26542693

RESUMO

BACKGROUND AND PURPOSE: The extent of ischemic injury in response to cerebral ischemia is known to be affected by native vasculature. However, the nonvascular and dynamic vascular responses and their genetic basis are not well understood. METHODS: We performed a genome-wide association study in 235 mice from 33 inbred strains using the middle cerebral artery occlusion model. Population structure and genetic relatedness were accounted for using the efficient mixed-model association method. Human orthologs to the genes associated with the significant and suggestive single-nucleotide polymorphisms from the mouse strain survey were examined in patients with M1 occlusions admitted with signs and symptoms of acute ischemic stroke. RESULTS: We identified 4 genome-wide significant and suggestive single-nucleotide polymorphisms to be associated with infarct volume in mice (rs3694965, P=2.17×10(-7); rs31924033, P=5.61×10(-6); rs32249495, P=2.08×10(-7); and rs3677406, P=9.56×10(-6)). rs32249495, which corresponds to angiopoietin-1 (ANGPT1), was also significant in the recessive model in humans, whereas rs1944577, which corresponds to ZBTB7C, was nominally significant in both the additive and dominant genetic models in humans. ZBTB7C was shown to be upregulated in endothelial cells using both in vitro and in vivo models of ischemia. CONCLUSIONS: Genetic variations of ANGPT1 and ZBTB7C are associated with increased infarct size in both mice and humans. ZBTB7C may modulate the ischemic response via neuronal apoptosis and dynamic collateralization and, in addition to ANGPT1, may serve as potential novel targets for treatments of cerebral ischemia.


Assuntos
Angiopoietina-1/genética , Isquemia Encefálica/genética , Estudo de Associação Genômica Ampla , Proteínas/genética , Animais , Isquemia Encefálica/diagnóstico , Feminino , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla/métodos , Humanos , Peptídeos e Proteínas de Sinalização Intracelular , Masculino , Camundongos , Camundongos da Linhagem 129 , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos DBA , Camundongos Endogâmicos NOD , Polimorfismo de Nucleotídeo Único/genética , Especificidade da Espécie
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