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1.
Brain Sci ; 14(3)2024 Feb 28.
Artigo em Inglês | MEDLINE | ID: mdl-38539619

RESUMO

In human stroke, brain swelling is an important predictor of neurological outcome and mortality, yet treatments to reduce or prevent brain swelling are extremely limited, due in part to an inadequate understanding of mechanisms. In preclinical studies on cerebroprotection in animal models of stroke, historically, the focus has been on reducing infarct size, and in most studies, a reduction in infarct size has been associated with a corresponding reduction in brain swelling. Unfortunately, such findings on brain swelling have little translational value for treating brain swelling in patients with stroke. This is because, in humans, brain swelling usually becomes evident, either symptomatically or radiologically, days after the infarct size has stabilized, requiring that the prevention or treatment of brain swelling target mechanism(s) that are independent of a reduction in infarct size. In this problematizing review, we highlight the often-neglected concept that brain edema and brain swelling are not simply secondary, correlative phenomena of stroke but distinct pathological entities with unique molecular and cellular mechanisms that are worthy of direct targeting. We outline the advances in approaches for the study of brain swelling that are independent of a reduction in infarct size. Although straightforward, the approaches reviewed in this study have important translational relevance for identifying novel treatment targets for post-ischemic brain swelling.

2.
Cells ; 12(18)2023 09 06.
Artigo em Inglês | MEDLINE | ID: mdl-37759444

RESUMO

Brain swelling is a major cause of death and disability in ischemic stroke. Drugs of the gliflozin class, which target the Na+-coupled D-glucose cotransporter, SGLT2, are approved for type 2 diabetes mellitus (T2DM) and may be beneficial in other conditions, but data in cerebral ischemia are limited. We studied murine models of cerebral ischemia with middle cerebral artery occlusion/reperfusion (MCAo/R). Slc5a2/SGLT2 mRNA and protein were upregulated de novo in astrocytes. Live cell imaging of brain slices from mice following MCAo/R showed that astrocytes responded to modest increases in D-glucose by increasing intracellular Na+ and cell volume (cytotoxic edema), both of which were inhibited by the SGLT2 inhibitor, canagliflozin. The effect of canagliflozin was studied in three mouse models of stroke: non-diabetic and T2DM mice with a moderate ischemic insult (MCAo/R, 1/24 h) and non-diabetic mice with a severe ischemic insult (MCAo/R, 2/24 h). Canagliflozin reduced infarct volumes in models with moderate but not severe ischemic insults. However, canagliflozin significantly reduced hemispheric swelling and improved neurological function in all models tested. The ability of canagliflozin to reduce brain swelling regardless of an effect on infarct size has important translational implications, especially in large ischemic strokes.


Assuntos
Edema Encefálico , Isquemia Encefálica , Diabetes Mellitus Tipo 2 , AVC Isquêmico , Inibidores do Transportador 2 de Sódio-Glicose , Animais , Camundongos , Canagliflozina/farmacologia , Canagliflozina/uso terapêutico , Edema Encefálico/tratamento farmacológico , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/tratamento farmacológico , Astrócitos , Transportador 2 de Glucose-Sódio , Inibidores do Transportador 2 de Sódio-Glicose/farmacologia , Inibidores do Transportador 2 de Sódio-Glicose/uso terapêutico , Glucose , Íons , Isquemia Encefálica/tratamento farmacológico , Infarto
3.
Chem Biol Interact ; 307: 167-178, 2019 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-31059704

RESUMO

Polyether compounds, a large group of biologically active metabolites produced by Streptomyces species have been reported to show a variety of bioactivity such as antibacterial, antifungal, antiparasitic, antiviral, and tumour cell cytotoxicity. Since some of these compounds target cancer stem cells and multi-drug resistant cancer cells, this family of compounds have become of high interest. In this study, three polyether-type metabolites (1-3), one of which was a new natural product (3), were isolated from the marine derived Streptomyces cacaoi via antimicrobial activity-guided fractionation studies. As several polyether compounds with structural similarity such as monensin have been linked with autophagy and cell death, we first assessed the cytotoxicity of these three compounds. Compounds 2 and 3, but not 1, were found to be cytotoxic in several cell lines with a higher potency towards cancer cells. Furthermore, 2 and 3 caused accumulation of both autophagy flux markers LC3-II and p62 along with cleavage of caspase-3, caspase-9 and poly (ADP-ribose) polymerase 1 (PARP-1). Interestingly, prolonged treatment of the compounds caused a dramatic downregulation of the proteins related to autophagasome formation in a dose dependent manner. Our findings provide insights on the molecular mechanisms of the polyether-type polyketides, and signify their potency as chemotherapeutic agents through inhibiting autophagy and inducing apoptosis.


Assuntos
Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Produtos Biológicos/farmacologia , Streptomyces/química , Produtos Biológicos/isolamento & purificação , Caspase 3/metabolismo , Caspase 9/metabolismo , Linhagem Celular Tumoral , Regulação para Baixo/efeitos dos fármacos , Humanos , Conformação Molecular , Poli(ADP-Ribose) Polimerases/metabolismo , Streptomyces/metabolismo
4.
J Neuropathol Exp Neurol ; 74(8): 835-49, 2015 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-26172285

RESUMO

The nonselective monovalent cation channel transient receptor potential melastatin 4 (Trpm4) is transcriptionally upregulated in neural and vascular cells in animal models of brain infarction. It associates with sulfonylurea receptor 1 (Sur1) to form Sur1-Trpm4 channels, which have critical roles in cytotoxic edema, cell death, blood-brain barrier breakdown, and vasogenic edema. We examined Trpm4 expression in postmortem brain specimens from 15 patients who died within the first 31 days of the onset of focal cerebral ischemia. We found increased Trpm4 protein expression in all cases using immunohistochemistry; transcriptional upregulation was confirmed using in situ hybridization of Trpm4 messenger RNA. Transient receptor potential melastatin 4 colocalized and coassociated with Sur1 within ischemic endothelial cells and neurons. Coexpression of Sur1 and Trpm4 in necrotic endothelial cells was also associated with vasogenic edema indicated by upregulated perivascular tumor necrosis factor, extravasation of serum immunoglobulin G, and associated inflammation. Upregulated Trpm4 protein was present up to 1 month after the onset of cerebral ischemia. In a rat model of middle cerebral artery occlusion stroke, pharmacologic channel blockade by glibenclamide, a selective inhibitor of sulfonylurea receptor, mitigated perivascular tumor necrosis factor labeling. Thus, upregulated Sur1-Trpm4 channels and associated blood-brain barrier disruption and cerebral edema suggest that pharmacologic targeting of this channel may represent a promising therapeutic strategy for the clinical management of patients with cerebral ischemia.


Assuntos
Infarto Cerebral/metabolismo , Receptores de Sulfonilureias/biossíntese , Canais de Cátion TRPM/biossíntese , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Modelos Animais de Doenças , Feminino , Humanos , Imuno-Histoquímica , Hibridização In Situ , Masculino , Pessoa de Meia-Idade , Ratos , Ratos Wistar , Regulação para Cima
5.
Pediatr Res ; 77(5): 663-73, 2015 May.
Artigo em Inglês | MEDLINE | ID: mdl-25665055

RESUMO

BACKGROUND: Three risk factors are associated with hemorrhagic forms of encephalopathy of prematurity (EP): (i) prematurity, (ii) in utero ischemia (IUI) or perinatal ischemia, and (iii) mechanical ventilation. We hypothesized that IUI would induce an angiogenic response marked by activation of vascular endothelial growth factor (VEGF) and matrix metalloproteinase-9 (MMP-9), the latter degrading vascular basement membrane and increasing vulnerability to raised intravenous pressure during positive pressure mechanical ventilation. METHODS: We studied a rat model of hemorrhagic-EP characterized by periventricular hemorrhages in which a 20-min episode of IUI is induced at E19, pups are born naturally at E21-22, and on P0, are subjected to a 20-min episode of positive pressure mechanical ventilation. Tissues were studied by H&E staining, immunolabeling, immunoblot, and zymography. RESULTS: Mechanical ventilation of rat pups 2-3 d after 20-min IUI caused widespread hemorrhages in periventricular tissues. IUI resulted in upregulation of VEGF and MMP-9. Zymography confirmed significantly elevated gelatinase activity. MMP-9 activation was accompanied by severe loss of MMP-9 substrates, collagen IV and laminin, in microvessels in periventricular areas. CONCLUSION: Our findings are consistent with the hypothesis that positive pressure mechanical ventilation of the newborn in the context of recent prenatal ischemia/hypoxia can predispose to periventricular hemorrhages.


Assuntos
Hemorragia/fisiopatologia , Isquemia/patologia , Neovascularização Patológica , Animais , Gasometria , Colágeno Tipo IV/química , Modelos Animais de Doenças , Eletrólitos , Feminino , Hemorragia/patologia , Hipóxia/patologia , Inflamação/patologia , Hemorragias Intracranianas , Laminina/química , Exposição Materna , Metaloproteinase 9 da Matriz/metabolismo , Gravidez , Prenhez , Ratos , Ratos Wistar , Respiração Artificial , Fatores de Risco , Fatores de Tempo , Fator A de Crescimento do Endotélio Vascular/metabolismo
6.
J Neurotrauma ; 31(14): 1292-304, 2014 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-24673157

RESUMO

Traumatic brain injury (TBI) caused by an explosive blast (blast-TBI) is postulated to result, in part, from transvascular transmission to the brain of a hydrodynamic pulse (a.k.a., volumetric blood surge, ballistic pressure wave, hydrostatic shock, or hydraulic shock) induced in major intrathoracic blood vessels. This mechanism of blast-TBI has not been demonstrated directly. We tested the hypothesis that a blast wave impacting the thorax would induce a hydrodynamic pulse that would cause pathological changes in the brain. We constructed a Thorax-Only Blast Injury Apparatus (TOBIA) and a Jugular-Only Blast Injury Apparatus (JOBIA). TOBIA delivered a collimated blast wave to the right lateral thorax of a rat, precluding direct impact on the cranium. JOBIA delivered a blast wave to the fluid-filled port of an extracorporeal intravenous infusion device whose catheter was inserted retrograde into the jugular vein, precluding lung injury. Long Evans rats were subjected to sublethal injury by TOBIA or JOBIA. Blast injury induced by TOBIA was characterized by apnea and diffuse bilateral hemorrhagic injury to the lungs associated with a transient reduction in pulse oximetry signals. Immunolabeling 24 h after injury by TOBIA showed up-regulation of tumor necrosis factor alpha, ED-1, sulfonylurea receptor 1 (Sur1), and glial fibrillary acidic protein in veins or perivenular tissues and microvessels throughout the brain. The perivenular inflammatory effects induced by TOBIA were prevented by ligating the jugular vein and were reproduced using JOBIA. We conclude that blast injury to the thorax leads to perivenular inflammation, Sur1 up-regulation, and reactive astrocytosis resulting from the induction of a hydrodynamic pulse in the vasculature.


Assuntos
Traumatismos por Explosões/patologia , Lesões Encefálicas/patologia , Animais , Modelos Animais de Doenças , Hidrodinâmica , Imuno-Histoquímica , Masculino , Ratos , Ratos Long-Evans , Tórax
7.
Biomarkers ; 19(2): 95-108, 2014 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-24499240

RESUMO

CONTEXT: Subarachnoid hemorrhage (SAH) has a high fatality rate and many suffer from delayed neurological deficits. Biomarkers may aid in the identification of high-risk patients, guide treatment/management and improve outcome. OBJECTIVE: The aim of this review was to summarize biomarkers of SAH associated with outcome. METHODS: An electronic database query was completed, including an additional review of reference lists to include all potential human studies. RESULTS: A total of 298 articles were identified; 112 were reviewed; 55 studies were included. CONCLUSION: This review details biomarkers of SAH that correlate with outcome. It provides the basis for research investigating their possible translation into the management of SAH patients.


Assuntos
Hemorragia Subaracnóidea/sangue , Animais , Biomarcadores/sangue , Humanos , Prognóstico , Hemorragia Subaracnóidea/diagnóstico , Hemorragia Subaracnóidea/terapia , Resultado do Tratamento
8.
Pharmaceuticals (Basel) ; 6(10): 1287-303, 2013 Oct 11.
Artigo em Inglês | MEDLINE | ID: mdl-24275850

RESUMO

First introduced into clinical practice in 1969, glibenclamide (US adopted name, glyburide) is known best for its use in the treatment of diabetes mellitus type 2, where it is used to promote the release of insulin by blocking pancreatic KATP [sulfonylurea receptor 1 (Sur1)-Kir6.2] channels. During the last decade, glibenclamide has received renewed attention due to its pleiotropic protective effects in acute CNS injury. Acting via inhibition of the recently characterized Sur1-Trpm4 channel (formerly, the Sur1-regulated NCCa-ATP channel) and, in some cases, via brain KATP channels, glibenclamide has been shown to be beneficial in several clinically relevant rodent models of ischemic and hemorrhagic stroke, traumatic brain injury, spinal cord injury, neonatal encephalopathy of prematurity, and metastatic brain tumor. Glibenclamide acts on microvessels to reduce edema formation and secondary hemorrhage, it inhibits necrotic cell death, it exerts potent anti-inflammatory effects and it promotes neurogenesis-all via inhibition of Sur1. Two clinical trials, one in TBI and one in stroke, currently are underway. These recent findings, which implicate Sur1 in a number of acute pathological conditions involving the CNS, present new opportunities to use glibenclamide, a well-known, safe pharmaceutical agent, for medical conditions that heretofore had few or no treatment options.

9.
Stroke ; 44(12): 3522-8, 2013 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-24114458

RESUMO

BACKGROUND AND PURPOSE: Subarachnoid hemorrhage (SAH) can leave patients with memory impairments that may not recover fully. Molecular mechanisms are poorly understood, and no treatment is available. The sulfonylurea receptor 1-transient receptor potential melastatin 4 (Sur1-Trpm4) channel plays an important role in acute central nervous system injury. We evaluated upregulation of Sur1-Trpm4 in humans with SAH and, in rat models of SAH, we examined Sur1-Trpm4 upregulation, its role in barrier dysfunction and neuroinflammation, and its consequences on spatial learning. METHODS: We used Förster resonance energy transfer to detect coassociated Sur1 and Trpm4 in human autopsy brains with SAH. We studied rat models of SAH involving filament puncture of the internal carotid artery or injection of blood into the subarachnoid space of the entorhinal cortex. In rats, we used Förster resonance energy transfer and coimmunoprecipitation to detect coassociated Sur1 and Trpm4, we measured immunoglobulin G extravasation and tumor necrosis α overexpression as measures of barrier dysfunction and neuroinflammation, and we assessed spatial learning and memory on days 7 to 19. RESULTS: Sur1-Trpm4 channels were upregulated in humans and rats with SAH. In rats, inhibiting Sur1 using antisense or the selective Sur1 inhibitor glibenclamide reduced SAH-induced immunoglobulin G extravasation and tumor necrosis α overexpression. In models with entorhinal SAH, rats treated with glibenclamide for 7 days after SAH exhibited better platform search strategies and better performance on incremental and rapid spatial learning than vehicle-treated controls. CONCLUSIONS: Sur1-Trpm4 channels are upregulated in humans and rats with SAH. Channel inhibition with glibenclamide may reduce neuroinflammation and the severity of cognitive deficits after SAH.


Assuntos
Transtornos Cognitivos/metabolismo , Encefalite/metabolismo , Hemorragia Subaracnóidea/metabolismo , Receptores de Sulfonilureias/antagonistas & inibidores , Canais de Cátion TRPM/antagonistas & inibidores , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Transtornos Cognitivos/genética , Transtornos Cognitivos/fisiopatologia , Encefalite/genética , Encefalite/fisiopatologia , Glibureto/farmacologia , Humanos , Aprendizagem em Labirinto/efeitos dos fármacos , Ratos , Hemorragia Subaracnóidea/genética , Hemorragia Subaracnóidea/fisiopatologia , Regulação para Cima/efeitos dos fármacos
10.
J Neuropathol Exp Neurol ; 72(9): 871-83, 2013 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-23965746

RESUMO

In animal models of stroke, sulfonylurea receptor 1 (Sur1), a member of the adenosine triphosphate binding cassette transporter gene family, is transcriptionally upregulated in neural and vascular cells in which it plays a leading role in edema formation and necrotic cell death. To date, expression of Sur1 in the brains of humans with cerebral infarcts has not been systematically evaluated. We examined Sur1 expression in postmortem specimens obtained from 13 patients within the first 31 days after focal infarcts, 5 patients with lacunar infarcts, and 6 normal control brains using immunohistochemistry. Elevated immunoreactivity for Sur1 was detected in all cases of focal infarcts, with 3 distinct temporal patterns of expression: 1) neurons and endothelium showed the greatest elevation during the first week, after which levels declined; 2) astrocytes and microglia/macrophages showed progressive increases during the first 31 days; and 3) neutrophils near the infarct showed prominent immunoreactivity that did not change over time. Upregulation of Sur1 was corroborated using in situ hybridization for Abcc8 mRNA. Sulfonylurea receptor 1 immunoreactivity in lacunar infarcts was less prominent and more sporadic than in nonlacunar infarcts. In conjunction with previous studies, these data suggest that Sur1 may be a promising treatment target in patients with acute cerebral infarction.


Assuntos
Transportadores de Cassetes de Ligação de ATP/metabolismo , Infarto Cerebral/metabolismo , Canais de Potássio Corretores do Fluxo de Internalização/metabolismo , Receptores de Droga/metabolismo , Transportadores de Cassetes de Ligação de ATP/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Antígenos CD , Antígenos de Diferenciação Mielomonocítica , Infarto Cerebral/patologia , Feminino , Humanos , Insulina/metabolismo , Masculino , Pessoa de Meia-Idade , Proteínas do Tecido Nervoso/metabolismo , Peroxidase/metabolismo , Molécula-1 de Adesão Celular Endotelial a Plaquetas/metabolismo , Canais de Potássio Corretores do Fluxo de Internalização/genética , Receptores de Droga/genética , Estatística como Assunto , Receptores de Sulfonilureias , Fatores de Tempo
11.
Brain Sci ; 3(1): 215-38, 2013 Mar 07.
Artigo em Inglês | MEDLINE | ID: mdl-23667741

RESUMO

We studied a model of hemorrhagic encephalopathy of prematurity (EP) that closely recapitulates findings in humans with hemorrhagic EP. This model involves tandem insults of 20 min intrauterine ischemia (IUI) plus an episode of elevated venous pressure induced by intraperitoneal glycerol on post-natal day (P) 0. We examined Sur1 expression, which is upregulated after focal ischemia but has not been studied after brief global ischemia including IUI. We found that 20 min IUI resulted in robust upregulation of Sur1 in periventricular microvessels and tissues. We studied tandem insult pups from untreated or vehicle-treated dams (TI-CTR), and tandem insult pups from dams administered a low-dose, non-hypoglycemogenic infusion of the Sur1 blocker, glibenclamide, for 1 week after IUI (TI-GLIB). Compared to pups from the TI-CTR group, pups from the TI-GLIB group had significantly fewer and less severe hemorrhages on P1, performed significantly better on the beam walk and accelerating Rotarod on P35 and in tests of thigmotaxis and rapid learning on P35-49, and had significantly greater body and brain weights at P52. We conclude that low-dose glibenclamide administered to the mother at the end of pregnancy protects pups subjected to IUI from post-natal events of elevated venous pressure and its consequences.

12.
Transl Stroke Res ; 3(Suppl 1): 155-65, 2012 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-22707992

RESUMO

Subarachnoid hemorrhage (SAH) can lead to disabling motor, cognitive, and neuropsychological abnormalities. Part of the secondary injury to cerebral tissues associated with SAH is attributable to the neuroinflammatory response induced by blood. Heparin is a pleiotropic compound that reduces inflammatory responses in conditions outside the central nervous system. Using a model of SAH devoid of global insult, we evaluated the effect of delayed intravenous (IV) infusion of heparin, at a dose that does not produce therapeutic anticoagulation, on neuroinflammation, myelin preservation, and apoptosis. Adult male rats underwent bilateral stereotactic injections of autologous blood (50 µL) into the subarachnoid space of the entorhinal cortex. The rats were implanted with mini-osmotic pumps that delivered either vehicle or unfractionated heparin (10 U/kg/h IV) beginning 12 h after SAH. No mechanical or hemorrhagic injury was observed in the hippocampus. In vehicle controls assessed at 48 h, SAH was associated with robust neuroinflammation in the adjacent cortex [neutrophils, activated phagocytic microglia, nuclear factor-kappa B, tumor necrosis factor-alpha, and interleukin-1beta] and neurodegeneration (Fluoro-Jade C staining and loss of NeuN). In the hippocampus, a muted neuroinflammatory response was indicated by Iba1-positive, ED1-negative microglia exhibiting an activated morphology. The perforant pathway showed Fluoro-Jade C staining and demyelination, and granule cells of the dentate gyrus had pyknotic nuclei, labeled with Fluoro-Jade C and showed upregulation of cleaved caspase-3, consistent with transsynaptic apoptosis. Administration of heparin significantly reduced neuroinflammation, demyelination, and transsynaptic apoptosis. We conclude that delayed IV infusion of low-dose unfractionated heparin may attenuate adverse neuroinflammatory effects of SAH.

13.
J Neurosurg Pediatr ; 8(6): 628-39, 2011 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-22132923

RESUMO

OBJECT: Encephalopathy of prematurity (EP) is common in preterm, low birth weight infants who require postnatal mechanical ventilation. The worst types of EP are the hemorrhagic forms, including choroid plexus, germinal matrix, periventricular, and intraventricular hemorrhages. Survivors exhibit life-long cognitive, behavioral, and motor abnormalities. Available preclinical models do not fully recapitulate the salient features of hemorrhagic EP encountered in humans. In this study, the authors evaluated a novel model using rats that featured tandem insults of transient prenatal intrauterine ischemia (IUI) plus transient postnatal raised intrathoracic pressure (RIP). METHODS: Timed-pregnant Wistar rats were anesthetized and underwent laparotomy on embryonic Day 19. Intrauterine ischemia was induced by clamping the uterine and ovarian vasculature for 20 minutes. Natural birth occurred on embryonic Day 22. Six hours after birth, the pups were subjected to an episode of RIP, induced by injecting glycerol (50%, 13 µl/g intraperitoneally). Control groups included naive, sham surgery, and IUI alone. Pathological, histological, and behavioral analyses were performed on pups up to postnatal Day 52. RESULTS: Compared with controls, pups subjected to IUI+RIP exhibited significant increases in postnatal mortality and hemorrhages in the choroid plexus, germinal matrix, and periventricular tissues as well as intraventricularly. On postnatal Days 35-52, they exhibited significant abnormalities involving complex vestibulomotor function and rapid spatial learning. On postnatal Day 52, the brain and body mass were significantly reduced. CONCLUSIONS: Tandem insults of IUI plus postnatal RIP recapitulate many features of the hemorrhagic forms of EP found in humans, suggesting that these insults in combination may play important roles in pathogenesis.


Assuntos
Animais Recém-Nascidos/lesões , Encefalopatias , Modelos Animais de Doenças , Doenças do Prematuro , Animais , Feminino , Idade Gestacional , Glicerol/farmacologia , Humanos , Recém-Nascido , Isquemia/fisiopatologia , Ligadura/métodos , Gravidez , Lesões Pré-Natais/fisiopatologia , Pressão , Ratos , Ratos Wistar , Solventes/farmacologia , Tórax/efeitos dos fármacos , Tórax/fisiopatologia , Útero/irrigação sanguínea
14.
Transl Stroke Res ; 2(2): 227-31, 2011 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-21731590

RESUMO

Intraventricular hemorrhage (IVH), which afflicts thousands of people of all ages every year, frequently results in the development of communicating hydrocephalus. Classically, IVH-induced hydrocephalus has been attributed to reduced resorption of cerebrospinal fluid (CSF) due to dysfunction of arachnoid granulations, but this explanation may be incomplete. We hypothesized that IVH would cause inflammation of the choroid plexus and of the ependymal lining of the ventricles, resulting in dysfunction of these barrier cells. Barrier dysfunction, in turn, would be expected to cause an increase in production of abnormal protein-rich CSF and transependymal migration of CSF. We tested this hypothesis using a rat model of IVH, in which 160 µl of autologous blood was infused into the lateral ventricle, resulting in a twofold increase in ventricular size 48 h later. In this model, we found significant activation of nuclear factor κB (NF-κB) signaling by the CSF barrier cells of the choroid plexus and ependymal lining. Moreover, these inflammatory changes were associated with abnormal uptake of serum-derived IgG by the barrier cells, a phenomenon closely linked to abnormal permeability of the blood-brain barrier. We conclude that inflammation marked by NF-κB signaling is a prominent feature after IVH and may account for certain pathophysiological sequelae associated with IVH.

15.
J Neurotrauma ; 28(10): 2155-69, 2011 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-21639724

RESUMO

Traumatic brain injury resulting from an explosive blast is one of the most serious wounds suffered by warfighters, yet the effects of explosive blast overpressure directly impacting the head are poorly understood. We developed a rodent model of direct cranial blast injury (dcBI), in which a blast overpressure could be delivered exclusively to the head, precluding indirect brain injury via thoracic transmission of the blast wave. We constructed and validated a Cranium Only Blast Injury Apparatus (COBIA) to deliver blast overpressures generated by detonating .22 caliber cartridges of smokeless powder. Blast waveforms generated by COBIA replicated those recorded within armored vehicles penetrated by munitions. Lethal dcBI (LD(50) ∼ 515 kPa) was associated with: (1) apparent brainstem failure, characterized by immediate opisthotonus and apnea leading to cardiac arrest that could not be overcome by cardiopulmonary resuscitation; (2) widespread subarachnoid hemorrhages without cortical contusions or intracerebral or intraventricular hemorrhages; and (3) no pulmonary abnormalities. Sub-lethal dcBI was associated with: (1) apnea lasting up to 15 sec, with transient abnormalities in oxygen saturation; (2) very few delayed deaths; (3) subarachnoid hemorrhages, especially in the path of the blast wave; (4) abnormal immunolabeling for IgG, cleaved caspase-3, and ß-amyloid precursor protein (ß-APP), and staining for Fluoro-Jade C, all in deep brain regions away from the subarachnoid hemorrhages, but in the path of the blast wave; and (5) abnormalities on the accelerating Rotarod that persisted for the 1 week period of observation. We conclude that exposure of the head alone to severe explosive blast predisposes to significant neurological dysfunction.


Assuntos
Traumatismos por Explosões/patologia , Lesões Encefálicas/patologia , Lesão Pulmonar Aguda/etiologia , Algoritmos , Animais , Axônios/patologia , Edema Encefálico/etiologia , Edema Encefálico/patologia , Modelos Animais de Doenças , Desenho de Equipamento , Frequência Cardíaca/fisiologia , Imuno-Histoquímica , Masculino , Neurônios/patologia , Oximetria , Equilíbrio Postural/fisiologia , Pressão , Ratos , Ratos Long-Evans , Reprodutibilidade dos Testes , Hemorragia Subaracnóidea/patologia , Testes de Função Vestibular , Vestíbulo do Labirinto/fisiopatologia
16.
Sci Transl Med ; 2(28): 28ra29, 2010 Apr 21.
Artigo em Inglês | MEDLINE | ID: mdl-20410530

RESUMO

Spinal cord injury (SCI) is typically complicated by progressive hemorrhagic necrosis, an autodestructive process of secondary injury characterized by progressive enlargement of a hemorrhagic contusion during the first several hours after trauma. We assessed the role of Abcc8, which encodes sulfonylurea receptor 1 (SUR1), in progressive hemorrhagic necrosis. After SCI, humans and rodents exhibited similar regional and cellular patterns of up-regulation of SUR1 and Abcc8 messenger RNA. Elimination of SUR1 in Abcc8(-/-) mice and in rats given antisense oligodeoxynucleotide against Abcc8 prevented progressive hemorrhagic necrosis, yielded significantly better neurological function, and resulted in lesions that were one-fourth to one-third the size of those in control animals. The beneficial effects of Abcc8 suppression were associated with prevention of oncotic (necrotic) death of capillary endothelial cells. Suppression of Abcc8 with antisense oligodeoxynucleotide after SCI presents an opportunity for reducing the devastating sequelae of SCI.


Assuntos
Transportadores de Cassetes de Ligação de ATP/metabolismo , Canais de Potássio Corretores do Fluxo de Internalização/metabolismo , Receptores de Droga/metabolismo , Traumatismos da Medula Espinal/patologia , Traumatismos da Medula Espinal/prevenção & controle , Transportadores de Cassetes de Ligação de ATP/genética , Animais , Modelos Animais de Doenças , Regulação da Expressão Gênica/efeitos dos fármacos , Glibureto/farmacologia , Hemorragia/complicações , Hemorragia/patologia , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Necrose , Canais de Potássio Corretores do Fluxo de Internalização/deficiência , Canais de Potássio Corretores do Fluxo de Internalização/genética , RNA Antissenso/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Ratos , Receptores de Droga/deficiência , Receptores de Droga/genética , Fator de Transcrição Sp1/metabolismo , Traumatismos da Medula Espinal/fisiopatologia , Receptores de Sulfonilureias , Resultado do Tratamento
17.
J Neurotrauma ; 26(12): 2233-43, 2009 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-19929375

RESUMO

Frontal impact, closed head trauma is a frequent cause of traumatic brain injury (TBI) in motor vehicle and sports accidents. Diffuse axonal injury (DAI) is common in humans and experimental animals, and results from shearing forces that develop within the anisotropic brain. Because the specific anisotropic properties of the brain are axis-dependent, the anatomical site where force is applied as well as the resultant acceleration, be it linear, rotational, or some combination, are important determinants of the resulting pattern of brain injury. Available rodent models of closed head injury do not reproduce the frontal impact commonly encountered in humans. Here we describe a new rat model of closed head injury that is a modification of the impact-acceleration model of Marmarou. In our model (the Maryland model), the impact force is applied to the anterior part of the cranium and produces TBI by causing anterior-posterior plus sagittal rotational acceleration of the brain inside the intact cranium. Skull fractures, prolonged apnea, and mortality were absent. The animals exhibited petechial hemorrhages, DAI marked by a bead-like pattern of beta-amyloid precursor protein (beta-APP) in damaged axons, and widespread upregulation of beta-APP in neurons, with regions affected including the orbitofrontal cortex (coup), corpus callosum, caudate, putamen, thalamus, cerebellum, and brainstem. Activated caspase-3 was prominent in hippocampal neurons and Purkinje cells at the grey-white matter junction of the cerebellum. Neurobehavioral dysfunction, manifesting as reduced spontaneous exploration, lasted more than 1 week. We conclude that the Maryland model produces diffuse injuries that may be relevant to human brain injury.


Assuntos
Lesões Encefálicas/patologia , Lesões Encefálicas/fisiopatologia , Encéfalo/patologia , Encéfalo/fisiopatologia , Traumatismos Cranianos Fechados/patologia , Traumatismos Cranianos Fechados/fisiopatologia , Aceleração/efeitos adversos , Precursor de Proteína beta-Amiloide/metabolismo , Animais , Axônios/metabolismo , Axônios/patologia , Biomarcadores/análise , Biomarcadores/metabolismo , Fenômenos Biomecânicos , Lesões Encefálicas/metabolismo , Caspase 3/metabolismo , Lesão Axonal Difusa/metabolismo , Lesão Axonal Difusa/patologia , Lesão Axonal Difusa/fisiopatologia , Modelos Animais de Doenças , Osso Frontal/lesões , Traumatismos Cranianos Fechados/metabolismo , Hipocampo/metabolismo , Hipocampo/patologia , Masculino , Neurônios/metabolismo , Neurônios/patologia , Física , Células de Purkinje/metabolismo , Células de Purkinje/patologia , Ratos , Ratos Long-Evans , Rotação/efeitos adversos
18.
J Neurotrauma ; 26(12): 2257-67, 2009 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-19604096

RESUMO

An important but poorly understood feature of traumatic brain injury (TBI) is the clinically serious problem of spatiotemporal progression ("blossoming") of a hemorrhagic contusion, a phenomenon we term progressive secondary hemorrhage (PSH). Molecular mechanisms of PSH are unknown and efforts to reduce it by promoting coagulation have met with equivocal results. We hypothesized that PSH might be due to upregulation and activation of sulfonylurea receptor 1 (SUR1)-regulated NC(Ca-ATP) channels in capillary endothelial cells, predisposing to oncotic death of endothelial cells and catastrophic failure of capillary integrity. Anesthetized adult male rats underwent left parietal craniectomy for induction of a focal cortical contusion. The regulatory subunit of the channel, SUR1, was prominently upregulated in capillaries of penumbral tissues surrounding the contusion. In untreated rats, PSH was characterized by progressive enlargement of the contusion deep into the site of cortical impact, including corpus callosum, hippocampus, and thalamus, by progressive accumulation of extravasated blood, with a doubling of the volume during the first 12 h after injury, and by capillary fragmentation in penumbral tissues. Block of SUR1 using low-dose (non-hypoglycemogenic) glibenclamide largely eliminated PSH and capillary fragmentation, and was associated with a significant reduction in the size of the necrotic lesion and in preservation of neurobehavioral function. Antisense oligodeoxynucleotide against SUR1, administered after injury, reduced both SUR1 expression and PSH, consistent with a requirement for transcriptional upregulation of SUR1. Our findings provide novel insights into molecular mechanisms responsible for PSH associated with hemorrhagic contusions, and point to SUR1 as a potential therapeutic target in TBI.


Assuntos
Transportadores de Cassetes de Ligação de ATP/metabolismo , Hemorragia Encefálica Traumática/metabolismo , Lesões Encefálicas/metabolismo , Encéfalo/metabolismo , Canais de Potássio Corretores do Fluxo de Internalização/metabolismo , Receptores de Droga/metabolismo , Transportadores de Cassetes de Ligação de ATP/antagonistas & inibidores , Transportadores de Cassetes de Ligação de ATP/genética , Animais , Barreira Hematoencefálica/metabolismo , Barreira Hematoencefálica/patologia , Barreira Hematoencefálica/fisiopatologia , Encéfalo/patologia , Encéfalo/fisiopatologia , Hemorragia Encefálica Traumática/patologia , Hemorragia Encefálica Traumática/fisiopatologia , Lesões Encefálicas/patologia , Lesões Encefálicas/fisiopatologia , Canais de Cálcio/metabolismo , Modelos Animais de Doenças , Regulação para Baixo/genética , Regulação para Baixo/fisiologia , Células Endoteliais/metabolismo , Glibureto/farmacologia , Hipoglicemiantes/farmacologia , Masculino , Fármacos Neuroprotetores/farmacologia , Oligodesoxirribonucleotídeos Antissenso/farmacologia , Canais de Potássio Corretores do Fluxo de Internalização/antagonistas & inibidores , Canais de Potássio Corretores do Fluxo de Internalização/genética , Ratos , Ratos Long-Evans , Receptores de Droga/antagonistas & inibidores , Receptores de Droga/genética , Receptores de Sulfonilureias , Regulação para Cima/fisiologia
19.
J Cereb Blood Flow Metab ; 29(2): 317-30, 2009 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-18854840

RESUMO

Subarachnoid hemorrhage (SAH) causes secondary brain injury due to vasospasm and inflammation. Here, we studied a rat model of mild-to-moderate SAH intended to minimize ischemia/hypoxia to examine the role of sulfonylurea receptor 1 (SUR1) in the inflammatory response induced by SAH. mRNA for Abcc8, which encodes SUR1, and SUR1 protein were abundantly upregulated in cortex adjacent to SAH, where tumor-necrosis factor-alpha (TNFalpha) and nuclear factor (NF)kappaB signaling were prominent. In vitro experiments confirmed that Abcc8 transcription is stimulated by TNFalpha. To investigate the functional consequences of SUR1 expression after SAH, we studied the effect of the potent, selective SUR1 inhibitor, glibenclamide. We examined barrier permeability (immunoglobulin G, IgG extravasation), and its correlate, the localization of the tight junction protein, zona occludens 1 (ZO-1). SAH caused a large increase in barrier permeability and disrupted the normal junctional localization of ZO-1, with glibenclamide significantly reducing both effects. In addition, SAH caused large increases in markers of inflammation, including TNFalpha and NFkappaB, and markers of cell injury or cell death, including IgG endocytosis and caspase-3 activation, with glibenclamide significantly reducing these effects. We conclude that block of SUR1 by glibenclamide may ameliorate several pathologic effects associated with inflammation that lead to cortical dysfunction after SAH.


Assuntos
Edema Encefálico/tratamento farmacológico , Edema Encefálico/enzimologia , Caspase 3/metabolismo , Glibureto/uso terapêutico , Inflamação/tratamento farmacológico , Hemorragia Subaracnóidea/tratamento farmacológico , Hemorragia Subaracnóidea/enzimologia , Transportadores de Cassetes de Ligação de ATP/genética , Transportadores de Cassetes de Ligação de ATP/metabolismo , Animais , Barreira Hematoencefálica/efeitos dos fármacos , Edema Encefálico/patologia , Lesões das Artérias Carótidas , Artéria Carótida Interna , Ativação Enzimática/efeitos dos fármacos , Hipóxia/patologia , Inflamação/enzimologia , Inflamação/patologia , Masculino , Canais de Potássio Corretores do Fluxo de Internalização/genética , Canais de Potássio Corretores do Fluxo de Internalização/metabolismo , Ratos , Ratos Wistar , Receptores de Droga/genética , Receptores de Droga/metabolismo , Hemorragia Subaracnóidea/patologia , Receptores de Sulfonilureias , Fator de Necrose Tumoral alfa/farmacologia , Regulação para Cima/genética
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