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1.
Ann Neurol ; 87(6): 939-949, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32239542

RESUMO

OBJECTIVE: Cortical spreading depression (CSD) underlies the neurobiology of migraine with aura (MWA). Animal studies reveal networks of microvessels linking brain-meninges-bone marrow. CSD activates the trigeminovascular system, evoking a meningeal inflammatory response. Accordingly, this study examines the upregulation of an inflammatory marker in extra-axial tissues in migraine with visual aura. METHODS: We used simultaneously acquired 11 C-PBR28 positron emission tomography/magnetic resonance imaging data of 18kDa translocator protein (an inflammatory marker) in MWA patients (n = 11) who experienced headaches and visual aura in the preceding month. We measured mean tracer uptake (standardized uptake value ratio [SUVR]) in 4 regions of interest comprising the meninges plus the adjacent overlying skull bone (parameningeal tissues [PMT]). These data were compared to healthy controls and patients with pain (chronic low back pain). RESULTS: MWA had significantly higher mean SUVR in PMT overlying occipital cortex than both other groups, although not in the PMT overlying 3 other cortical areas. A positive correlation was also found between the number of visual auras and tracer uptake in occipital PMT. INTERPRETATION: A strong persistent extra-axial inflammatory signal was found in meninges and calvarial bone overlying the occipital lobe in migraine with visual auras. Our findings are reminiscent of CSD-induced meningeal inflammation and provide the first imaging evidence implicating inflammation in the pathophysiology of migraine meningeal symptoms. We suspect that this inflammatory focus results from a signal that migrates from underlying brain and if so, may implicate newly discovered bridging vessels that crosstalk between brain and skull marrow, a finding of potential relevance to migraine and other neuroinflammatory brain disorders. ANN NEUROL 2020;87:939-949.

2.
Lancet Neurol ; 18(8): 795-804, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31160203

RESUMO

The underlying causes of migraine headache remained enigmatic for most of the 20th century. In 1979, The Lancet published a novel hypothesis proposing an integral role for the neuropeptide-containing trigeminal nerve. This hypothesis led to a transformation in the migraine field and understanding of key concepts surrounding migraine, including the role of neuropeptides and their release from meningeal trigeminal nerve endings in the mechanism of migraine, blockade of neuropeptide release by anti-migraine drugs, and activation and sensitisation of trigeminal afferents by meningeal inflammatory stimuli and upstream role of intense brain activity. The study of neuropeptides provided the first evidence that antisera directed against calcitonin gene-related peptide (CGRP) and substance P could neutralise their actions. Successful therapeutic strategies using humanised monoclonal antibodies directed against CGRP and its receptor followed from these findings. Nowadays, 40 years after the initial proposal, the trigeminovascular system is widely accepted as having a fundamental role in this highly complex neurological disorder and provides a road map for future migraine therapies.

3.
Circ Res ; 124(9): 1372-1385, 2019 04 26.
Artigo em Inglês | MEDLINE | ID: mdl-30782088

RESUMO

RATIONALE: After a stroke, patients frequently experience altered systemic immunity resulting in peripheral immunosuppression and higher susceptibility to infections, which is at least partly attributed to lymphopenia. The mechanisms that profoundly change the systemic leukocyte repertoire after stroke are incompletely understood. Emerging evidence indicates that stroke alters hematopoietic output of the bone marrow. OBJECTIVE: To explore the mechanisms that lead to defects of B lymphopoiesis after ischemic stroke. METHODS AND RESULTS: We here report that ischemic stroke triggers brain-bone marrow communication via hormonal long-range signals that regulate hematopoietic B lineage decisions. Bone marrow fluorescence-activated cell sorter analyses and serial intravital microscopy indicate that transient middle cerebral artery occlusion in mice arrests B-cell development beginning at the pro-B-cell stage. This phenotype was not rescued in Myd88-/- and TLR4-/- mice with disrupted TLR (Toll-like receptor) signaling or after blockage of peripheral sympathetic nerves. Mechanistically, we identified stroke-induced glucocorticoid release as the main instigator of B lymphopoiesis defects. B-cell lineage-specific deletion of the GR (glucocorticoid receptor) in CD19-Cre loxP Nr3c1 mice attenuated lymphocytopenia after transient middle cerebral artery. In 20 patients with acute stroke, increased cortisol levels inversely correlated with blood lymphocyte numbers. CONCLUSIONS: Our data demonstrate that the hypothalamic-pituitary-adrenal axis mediates B lymphopoiesis defects after ischemic stroke.

4.
Alzheimers Dement ; 15(1): 158-167, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30642436

RESUMO

Increasing evidence recognizes Alzheimer's disease (AD) as a multifactorial and heterogeneous disease with multiple contributors to its pathophysiology, including vascular dysfunction. The recently updated AD Research Framework put forth by the National Institute on Aging-Alzheimer's Association describes a biomarker-based pathologic definition of AD focused on amyloid, tau, and neuronal injury. In response to this article, here we first discussed evidence that vascular dysfunction is an important early event in AD pathophysiology. Next, we examined various imaging sequences that could be easily implemented to evaluate different types of vascular dysfunction associated with, and/or contributing to, AD pathophysiology, including changes in blood-brain barrier integrity and cerebral blood flow. Vascular imaging biomarkers of small vessel disease of the brain, which is responsible for >50% of dementia worldwide, including AD, are already established, well characterized, and easy to recognize. We suggest that these vascular biomarkers should be incorporated into the AD Research Framework to gain a better understanding of AD pathophysiology and aid in treatment efforts.


Assuntos
Doença de Alzheimer/fisiopatologia , Biomarcadores , Doenças Vasculares/fisiopatologia , Substância Branca/patologia , Doença de Alzheimer/patologia , Peptídeos beta-Amiloides/metabolismo , Barreira Hematoencefálica/metabolismo , Encéfalo/patologia , Circulação Cerebrovascular/fisiologia , Humanos , National Institute on Aging (U.S.) , Estados Unidos
5.
J Cereb Blood Flow Metab ; 39(4): 740-750, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-29651899

RESUMO

Several factors that modulate migraine, a common primary headache disorder, also affect susceptibility to cortical spreading depolarization (CSD). CSD is a wave of neuronal and glial depolarization and thought to underlie the migraine aura and possibly headache. Here, we tested whether caffeine, known to alleviate or trigger headache after acute exposure or chronic use/withdrawal, respectively, modulates CSD. We injected C57BL/6J mice with caffeine (30, 60, or 120 mg/kg; i.p.) once ( acute) or twice per day for one or two weeks ( chronic). Susceptibility to CSD was evaluated by measuring the electrical CSD threshold and by assessing KCl-induced CSD. Simultaneous laser Doppler flowmetry was used to assess CSD-induced cortical blood flow changes. Recordings were performed 15 min after caffeine/vehicle administration, or 24 h after the last dose of chronic caffeine in the withdrawal group. The latter paradigm was also tested in mice carrying the familial hemiplegic migraine type 1 R192Q missense mutation, considered a valid migraine model. Neither acute/chronic administration nor withdrawal of caffeine affected CSD susceptibility or related cortical blood flow changes, either in WT or R192Q mice. Hence, adverse or beneficial effects of caffeine on headache seem unrelated to CSD pathophysiology, consistent with the non-migrainous clinical presentation of caffeine-related headache.

6.
J Cereb Blood Flow Metab ; 39(9): 1864-1877, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-29673284

RESUMO

Myeloperoxidase (MPO) is a pro-inflammatory enzyme abundantly secreted by activated myeloid cells after stroke. We show that when MPO activity is either blocked by the specific inhibitor 4-aminobenzoic acid hydrazide (ABAH) in wildtype (WT) mice or congenitally absent (MPO-/-), there was decreased cell loss, including degenerating neurons and oligodendrocytes, in the ischemic brains compared to vehicle-treated WT mice after stroke. MPO inhibition also reduced the number of activated myeloid cells after ischemia. MPO inhibition increased cytoprotective heat shock protein 70 (Hsp70) by 70% and p-Akt by 60%, while decreased the apoptotic marker p53 level by 62%, compared to vehicle-treated mice after ischemia. Similarly, MPO inhibition increased the number of Hsp70+/NeuN+ cells after stroke by 60%. Notably, MPO inhibition significantly improved neurological outcome compared with the vehicle-treated group after stroke. We further found longer treatment periods resulted in larger reduction of infarct size and greater neurobehavioral improvement from MPO inhibition, even when given days after stroke. Therefore, MPO inhibition with ABAH or MPO deficiency creates a protective environment that decreased inflammatory cell recruitment and increased expression of survival factors to improve functional outcome. MPO inhibition may represent a promising therapeutic target for stroke therapy, possibly even days after stroke has occurred.

8.
Nat Neurosci ; 21(9): 1209-1217, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-30150661

RESUMO

Innate immune cells recruited to inflammatory sites have short life spans and originate from the marrow, which is distributed throughout the long and flat bones. While bone marrow production and release of leukocyte increases after stroke, it is currently unknown whether its activity rises homogeneously throughout the entire hematopoietic system. To address this question, we employed spectrally resolved in vivo cell labeling in the murine skull and tibia. We show that in murine models of stroke and aseptic meningitis, skull bone marrow-derived neutrophils are more likely to migrate to the adjacent brain tissue than cells that reside in the tibia. Confocal microscopy of the skull-dura interface revealed myeloid cell migration through microscopic vascular channels crossing the inner skull cortex. These observations point to a direct local interaction between the brain and the skull bone marrow through the meninges.


Assuntos
Medula Óssea/fisiologia , Movimento Celular/fisiologia , Células Mieloides/fisiologia , Crânio/fisiologia , Adulto , Animais , Medula Óssea/ultraestrutura , Feminino , Humanos , Inflamação/patologia , Masculino , Meningite Asséptica/patologia , Camundongos , Camundongos Endogâmicos C57BL , Pessoa de Meia-Idade , Células Mieloides/ultraestrutura , Neutrófilos , Crânio/citologia , Crânio/ultraestrutura , Acidente Vascular Cerebral/patologia , Tíbia/fisiologia , Tíbia/ultraestrutura , Tomografia Computadorizada por Raios X
9.
Circ J ; 82(4): 1195-1204, 2018 03 23.
Artigo em Inglês | MEDLINE | ID: mdl-29353861

RESUMO

BACKGROUND: Rho-associated kinases (ROCK1 and ROCK2) are important regulators of the actin cytoskeleton and endothelial nitric oxide synthase (eNOS). Because the phosphorylation of eukaryotic elongation factor-1A1 (eEF1A1) by ROCK2 is critical for eNOS expression, we hypothesized that this molecular pathway may play a critical role in neuroprotection following focal cerebral ischemia.Methods and Results:Adult male wild-type (WT) and mutant ROCK2 and eNOS-/-mice were subjected to middle cerebral artery occlusion (MCAO), and cerebral infarct size, neurological deficit and absolute cerebral blood flow were measured. In addition, aortic endothelium-dependent response to acetylcholine, NG-nitro-L-arginine methyl ester (L-NAME) and sodium nitroprusside were assessed ex vivo. Endothelial cells from mouse brain or heart were used to measure eNOS and eEF1A activity, as well as NO production and eNOS mRNA half-life. In global hemizygous ROCK2+/-and endothelial-specific EC-ROCK2-/-mice, eNOS mRNA stability and eNOS expression were increased, which correlated with enhanced endothelium-dependent relaxation and neuroprotection following focal cerebral ischemia. Indeed, when ROCK2+/-mice were place on an eNOS-/-background, the neuroprotective effects observed in ROCK2+/-mice were abolished. CONCLUSIONS: These findings indicate that the phosphorylation of eEF1A1 by ROCK2 is physiologically important for eNOS expression and NO-mediated neuroprotection, and suggest that targeting endothelial ROCK2 and eEF1A may have therapeutic benefits in ischemic stroke and cardiovascular disease.


Assuntos
Neuroproteção/efeitos dos fármacos , Óxido Nítrico Sintase Tipo III/fisiologia , Quinases Associadas a rho/deficiência , Animais , Isquemia Encefálica/tratamento farmacológico , Doenças Cardiovasculares/tratamento farmacológico , Camundongos , Óxido Nítrico , Óxido Nítrico Sintase Tipo III/genética , Óxido Nítrico Sintase Tipo III/metabolismo , Fator 1 de Elongação de Peptídeos/metabolismo , Fosforilação , Regulação para Cima , Quinases Associadas a rho/fisiologia
12.
Brain ; 140(6): 1643-1656, 2017 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-28430869

RESUMO

Spreading depolarization is a wave of neuronal and glial depolarization. Within minutes after spreading depolarization, the neuronal hemichannel pannexin 1 (PANX1) opens and forms a pore complex with the ligand-gated cation channel P2X7, allowing the release of excitatory neurotransmitters to sustain spreading depolarization and activate neuroinflammation. Here, we explore the hypothesis that the P2X7-PANX1 pore complex is a critical determinant of spreading depolarization susceptibility with important consequences for neuroinflammation and trigeminovascular activation. We found that genetic loss of function or ablation of the P2x7 gene inhibits spreading depolarization. Moreover, pharmacological suppression of the P2X7-PANX1 pore complex inhibits spreading depolarization in mice carrying the human familial hemiplegic migraine type 1 R192Q missense mutation as well as in wild-type mice and rats. Pore inhibitors elevate the electrical threshold for spreading depolarization, and reduce spreading depolarization frequency and amplitude. Pore inhibitors also suppress downstream consequences of spreading depolarization such as upregulation of interleukin-1 beta, inducible nitric oxide synthase and cyclooxygenase-2 in the cortex after spreading depolarization. In addition, they inhibit surrogates for trigeminovascular activation, including expression of calcitonin gene-related peptide in the trigeminal ganglion and c-Fos in the trigeminal nucleus caudalis. Our results are consistent with the hypothesis that the P2X7-PANX1 pore complex is a critical determinant of spreading depolarization susceptibility and its downstream consequences, of potential relevance to its signature disorders such as migraine.


Assuntos
Ataxia Cerebelar/tratamento farmacológico , Córtex Cerebral/efeitos dos fármacos , Conexinas/efeitos dos fármacos , Depressão Alastrante da Atividade Elétrica Cortical/efeitos dos fármacos , Inibidores Enzimáticos/farmacologia , Inflamação/tratamento farmacológico , Transtornos de Enxaqueca/tratamento farmacológico , Proteínas do Tecido Nervoso/efeitos dos fármacos , Antagonistas do Receptor Purinérgico P2X/farmacologia , Receptores Purinérgicos P2X7/efeitos dos fármacos , Animais , Conexinas/antagonistas & inibidores , Modelos Animais de Doenças , Humanos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteínas do Tecido Nervoso/antagonistas & inibidores , Ratos , Ratos Sprague-Dawley
13.
J Pharmacol Exp Ther ; 359(2): 262-272, 2016 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-27550713

RESUMO

The relationship between inflammation and neurogenesis in stroke is currently not well understood. Focal ischemia enhances cell proliferation and neurogenesis in the neurogenic regions, including the subventricular zone (SVZ), dentate gyrus, as well as the non-neurogenic striatum, and cortex in the ischemic hemisphere. Myeloperoxidase (MPO) is a potent oxidizing enzyme secreted during inflammation by activated leukocytes, and its enzymatic activity is highly elevated after stroke. In this study, we investigated whether the inhibition of MPO activity by a specific irreversible inhibitor, 4-aminobenzoic acid hydrazide (ABAH) (MPO-/- mice) can increase neurogenesis after transient middle cerebral artery occlusion in mice. ABAH administration increased the number of proliferating bromodeoxyuridine (BrdU)-positive cells expressing markers for neural stems cells, astrocytes, neuroprogenitor cells (Nestin), and neuroblasts (doublecortin) in the ischemic SVZ, anterior SVZ, striatum, and cortex. MPO inhibition also increased levels of brain-derived neurotrophic factor, phosphorylation of cAMP response element-binding protein (Ser133), acetylated H3, and NeuN to promote neurogenesis in the ischemic SVZ. ABAH treatment also increased chemokine CXC receptor 4 expression in the ischemic SVZ. MPO-deficient mice treated with vehicle or ABAH both showed similar effects on the number of BrdU+ cells in the ischemic hemisphere, demonstrating that ABAH is specific to MPO. Taken together, our results underscore a detrimental role of MPO activity to postischemia neurogenesis and that a strategy to inhibit MPO activity can increase cell proliferation and improve neurogenesis after ischemic stroke.


Assuntos
Ácido 4-Aminobenzoico/farmacologia , Inibidores Enzimáticos/farmacologia , Infarto da Artéria Cerebral Média/complicações , Neurogênese/efeitos dos fármacos , Peroxidase/antagonistas & inibidores , Acidente Vascular Cerebral/complicações , Acidente Vascular Cerebral/patologia , Acetilação/efeitos dos fármacos , Animais , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Proliferação de Células/efeitos dos fármacos , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Proteínas de Ligação a DNA , Histonas/metabolismo , Ventrículos Laterais/patologia , Masculino , Metaloproteinase 9 da Matriz/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Neostriado/patologia , Proteínas do Tecido Nervoso/metabolismo , Proteínas Nucleares/metabolismo , Receptores CXCR4/metabolismo , Recuperação de Função Fisiológica/efeitos dos fármacos , Acidente Vascular Cerebral/fisiopatologia
14.
Neuron ; 85(5): 1117-31, 2015 Mar 04.
Artigo em Inglês | MEDLINE | ID: mdl-25741731

RESUMO

UNLABELLED: Peri-infarct depolarizations (PIDs) are seemingly spontaneous spreading depression-like waves that negatively impact tissue outcome in both experimental and human stroke. Factors triggering PIDs are unknown. Here, we show that somatosensory activation of peri-infarct cortex triggers PIDs when the activated cortex is within a critical range of ischemia. We show that the mechanism involves increased oxygen utilization within the activated cortex, worsening the supply-demand mismatch. We support the concept by clinical data showing that mismatch predisposes stroke patients to PIDs as well. Conversely, transient worsening of mismatch by episodic hypoxemia or hypotension also reproducibly triggers PIDs. Therefore, PIDs are triggered upon supply-demand mismatch transients in metastable peri-infarct hot zones due to increased demand or reduced supply. Based on the data, we propose that minimizing sensory stimulation and hypoxic or hypotensive transients in stroke and brain injury would reduce PID incidence and their adverse impact on outcome.


Assuntos
Infarto Cerebral/metabolismo , Depressão Alastrante da Atividade Elétrica Cortical/fisiologia , Infarto da Artéria Cerebral Média/metabolismo , Córtex Somatossensorial/metabolismo , Adulto , Idoso , Animais , Infarto Cerebral/patologia , Feminino , Humanos , Infarto da Artéria Cerebral Média/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Pessoa de Meia-Idade , Córtex Somatossensorial/patologia
15.
Circ Res ; 116(3): 407-17, 2015 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-25362208

RESUMO

RATIONALE: The mechanisms leading to an expanded neutrophil and monocyte supply after stroke are incompletely understood. OBJECTIVE: To test the hypothesis that transient middle cerebral artery occlusion (tMCAO) in mice leads to activation of hematopoietic bone marrow stem cells. METHODS AND RESULTS: Serial in vivo bioluminescence reporter gene imaging in mice with tMCAO revealed that bone marrow cell cycling peaked 4 days after stroke (P<0.05 versus pre tMCAO). Flow cytometry and cell cycle analysis showed activation of the entire hematopoietic tree, including myeloid progenitors. The cycling fraction of the most upstream hematopoietic stem cells increased from 3.34%±0.19% to 7.32%±0.52% after tMCAO (P<0.05). In vivo microscopy corroborated proliferation of adoptively transferred hematopoietic progenitors in the bone marrow of mice with stroke. The hematopoietic system's myeloid bias was reflected by increased expression of myeloid transcription factors, including PU.1 (P<0.05), and by a decline in lymphocyte precursors. In mice after tMCAO, tyrosine hydroxylase levels in sympathetic fibers and bone marrow noradrenaline levels rose (P<0.05, respectively), associated with a decrease of hematopoietic niche factors that promote stem cell quiescence. In mice with genetic deficiency of the ß3 adrenergic receptor, hematopoietic stem cells did not enter the cell cycle in increased numbers after tMCAO (naive control, 3.23±0.22; tMCAO, 3.74±0.33, P=0.51). CONCLUSIONS: Ischemic stroke activates hematopoietic stem cells via increased sympathetic tone, leading to a myeloid bias of hematopoiesis and higher bone marrow output of inflammatory Ly6C(high) monocytes and neutrophils.


Assuntos
Infarto da Artéria Cerebral Média/patologia , Células-Tronco Mesenquimais/fisiologia , Mielopoese , Fibras Adrenérgicas/metabolismo , Fibras Adrenérgicas/fisiologia , Animais , Medula Óssea/metabolismo , Medula Óssea/patologia , Ciclo Celular , Infarto da Artéria Cerebral Média/metabolismo , Células-Tronco Mesenquimais/metabolismo , Células-Tronco Mesenquimais/patologia , Camundongos , Camundongos Endogâmicos C57BL , Norepinefrina/metabolismo , Receptores Adrenérgicos beta 3/genética , Receptores Adrenérgicos beta 3/metabolismo , Nicho de Células-Tronco , Fatores de Transcrição/metabolismo , Tirosina 3-Mono-Oxigenase/metabolismo
16.
J Cereb Blood Flow Metab ; 35(3): 485-93, 2015 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-25515211

RESUMO

Few effective treatment options exist for stroke beyond the hyperacute period. Radical generation and myeloperoxidase (MPO) have been implicated in stroke. We investigated whether pharmacologic reduction or gene deletion of this highly oxidative enzyme reduces infarct propagation and improves outcome in the transient middle cerebral artery occlusion mouse model (MCAO). Mice were treated with 4-aminobenzoic acid hydrazide (ABAH), a specific irreversible MPO inhibitor. Three treatment regimens were used: (1) daily throughout the 21-day observational period, (2) during the acute stage (first 24 hours), or (3) during the subacute stage (daily starting on day 2). We found elevated MPO activity in ipsilateral brain 3 to 21 days after ischemia. 4-Aminobenzoic acid hydrazide reduced enzyme activity by 30% to 40% and final lesion volume by 60% (P<0.01). The MPO-knockout (KO) mice subjected to MCAO also showed a similar reduction in the final lesion volume (P<0.01). The ABAH treatment or MPO-KO mice also improved neurobehavioral outcome (P<0.001) and survival (P=0.01), but ABAH had no additional beneficial effects in MPO-KO mice, confirming specificity of ABAH. Interestingly, inhibiting MPO activity during the subacute stage recapitulated most of the therapeutic benefit of continuous MPO inhibition, suggesting that MPO-targeted therapies could be useful when given after 24 hours of stroke onset.


Assuntos
Encéfalo/enzimologia , Encéfalo/patologia , Peroxidase/metabolismo , Acidente Vascular Cerebral/enzimologia , Acidente Vascular Cerebral/patologia , Animais , Modelos Animais de Doenças , Inibidores Enzimáticos/farmacologia , Imagem por Ressonância Magnética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout
17.
Nat Rev Neurosci ; 15(6): 379-93, 2014 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-24857965

RESUMO

Punctuated episodes of spreading depolarizations erupt in the brain, encumbering tissue structure and function, and raising fascinating unanswered questions concerning their initiation and propagation. Linked to migraine aura and headache, cortical spreading depression contributes to the morbidity in the world's migraine with aura population. Even more ominously, erupting spreading depolarizations accelerate tissue damage during brain injury. The once-held view that spreading depolarizations may not exist in the human brain has changed, largely because of the discovery of migraine genes that confer cortical spreading depression susceptibility, the application of sophisticated imaging tools and efforts to interrogate their impact in the acutely injured human brain.


Assuntos
Lesões Encefálicas/fisiopatologia , Córtex Cerebral/fisiopatologia , Depressão Alastrante da Atividade Elétrica Cortical/fisiologia , Transtornos de Enxaqueca/fisiopatologia , Animais , Lesões Encefálicas/patologia , Córtex Cerebral/citologia , Córtex Cerebral/metabolismo , Depressão Alastrante da Atividade Elétrica Cortical/genética , Humanos , Transtornos de Enxaqueca/patologia
18.
Stroke ; 45(5): 1468-73, 2014 May.
Artigo em Inglês | MEDLINE | ID: mdl-24723319

RESUMO

BACKGROUND AND PURPOSE: Small subcortical white matter infarcts are a common stroke subtype often associated with cognitive deficits. The lack of relevant models confined to white matter has limited the investigation of its pathophysiology. Here, we examine tissue and functional outcome after an ischemic lesion within corpus callosum in wild-type (WT) mice and in mice null for a gene, NOTCH3, linked to white matter ischemic injury in patients. METHODS: WT and NOTCH3 knockout mice were subjected to stereotactic microinjections of the potent vasoconstrictor endothelin-1 at the level of periventricular white matter to induce a focal ischemic lesion. Infarct location was confirmed by MRI, and brains were examined for lesion size and histology; behavioral deficits were assessed ≤1 month in WT mice. RESULTS: Ischemic damage featured an early cerebral blood flow deficit, blood-brain barrier opening, and a lesion largely confined to white matter. At later stages, myelin and axonal degeneration and microglial/macrophage infiltration were found. WT mice displayed prolonged cognitive deficit when tested using a novel object recognition task. NOTCH3 mutants showed larger infarcts and greater cognitive deficit at 7 days post stroke. CONCLUSIONS: Taken together, these data show the usefulness of microinjections of endothelin-1 into periventricular white matter to study focal infarcts and cognitive deficit in WT mice. In short-term studies, stroke outcome was worse in NOTCH3 null mice, consistent with the notion that the lack of the NOTCH3 receptor affects white matter stroke susceptibility.


Assuntos
Infarto Cerebral/fisiopatologia , Corpo Caloso/fisiopatologia , Leucoencefalopatias/fisiopatologia , Transtornos da Memória/fisiopatologia , Receptores Notch/deficiência , /fisiologia , Animais , Comportamento Animal/fisiologia , Infarto Cerebral/genética , Infarto Cerebral/patologia , Corpo Caloso/efeitos dos fármacos , Corpo Caloso/patologia , Modelos Animais de Doenças , Endotelina-1/administração & dosagem , Endotelina-1/farmacologia , Predisposição Genética para Doença/genética , Leucoencefalopatias/genética , Leucoencefalopatias/patologia , Masculino , Transtornos da Memória/genética , Transtornos da Memória/patologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Distribuição Aleatória , Receptor Notch3 , Receptores Notch/genética
19.
JAMA Neurol ; 71(2): 233-6, 2014 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-24296962

RESUMO

Innate immune cells are critically involved in ischemic complications of atherosclerosis. While new insight emerged on the origin and role of leukocytes in steady state, the knowledge about myeloid cells' sources, functions, and fate after stroke is limited. In our review, we highlight open questions in this important area while examining potential parallels in the immune response after stroke and myocardial infarction. We stress the need to better understand systemic interactions between ischemic tissue, immunity, and hematopoiesis, as turnover of leukocytes in inflammatory sites can be rapid, and cell production and supply may serve as future therapeutic targets to modulate inflammation in the vessel wall, brain, and heart.


Assuntos
Isquemia Encefálica/imunologia , Imunidade Inata/imunologia , Isquemia Miocárdica/imunologia , Animais , Isquemia Encefálica/patologia , Humanos , Leucócitos Mononucleares/imunologia , Monócitos/imunologia , Isquemia Miocárdica/patologia
20.
Neuron ; 80(2): 270-4, 2013 Oct 16.
Artigo em Inglês | MEDLINE | ID: mdl-24139032

RESUMO

The Brain Research through Advancing Innovative Neurotechnologies (BRAIN) Initiative has focused scientific attention on the necessary tools to understand the human brain and mind. Here, we outline our collective vision for what we can achieve within a decade with properly targeted efforts and discuss likely technological deliverables and neuroscience progress.


Assuntos
Mapeamento Encefálico/tendências , Neurociências/tendências , Animais , Pesquisa Biomédica/métodos , Pesquisa Biomédica/tendências , Mapeamento Encefálico/métodos , Humanos , Neurociências/métodos
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