RESUMO
Failed regeneration of myelin around neuronal axons following central nervous system damage contributes to nerve dysfunction and clinical decline in various neurological conditions, for which there is an unmet therapeutic demand. Here, we show that interaction between glial cells - astrocytes and mature myelin-forming oligodendrocytes - is a determinant of remyelination. Using in vivo/ ex vivo/ in vitro rodent models, unbiased RNA sequencing, functional manipulation, and human brain lesion analyses, we discover that astrocytes support the survival of regenerating oligodendrocytes, via downregulation of the Nrf2 pathway associated with increased astrocytic cholesterol biosynthesis pathway activation. Remyelination fails following sustained astrocytic Nrf2 activation in focally-lesioned male mice yet is restored by either cholesterol biosynthesis/efflux stimulation, or Nrf2 inhibition using the existing therapeutic Luteolin. We identify that astrocyte-oligodendrocyte interaction regulates remyelination, and reveal a drug strategy for central nervous system regeneration centred on targeting this interaction.
Assuntos
Astrócitos , Fator 2 Relacionado a NF-E2 , Masculino , Camundongos , Animais , Humanos , Astrócitos/metabolismo , Fator 2 Relacionado a NF-E2/genética , Fator 2 Relacionado a NF-E2/metabolismo , Sistema Nervoso Central/metabolismo , Oligodendroglia/metabolismo , Bainha de Mielina/metabolismo , Regeneração Nervosa/fisiologia , Colesterol/metabolismoRESUMO
Alzheimer's disease (AD) alters astrocytes, but the effect of Aß and Tau pathology is poorly understood. TRAP-seq translatome analysis of astrocytes in APP/PS1 ß-amyloidopathy and MAPTP301S tauopathy mice revealed that only Aß influenced expression of AD risk genes, but both pathologies precociously induced age-dependent changes, and had distinct but overlapping signatures found in human post-mortem AD astrocytes. Both Aß and Tau pathology induced an astrocyte signature involving repression of bioenergetic and translation machinery, and induction of inflammation pathways plus protein degradation/proteostasis genes, the latter enriched in targets of inflammatory mediator Spi1 and stress-activated cytoprotective Nrf2. Astrocyte-specific Nrf2 expression induced a reactive phenotype which recapitulated elements of this proteostasis signature, reduced Aß deposition and phospho-tau accumulation in their respective models, and rescued brain-wide transcriptional deregulation, cellular pathology, neurodegeneration and behavioural/cognitive deficits. Thus, Aß and Tau induce overlapping astrocyte profiles associated with both deleterious and adaptive-protective signals, the latter of which can slow patho-progression.
Assuntos
Doença de Alzheimer/genética , Precursor de Proteína beta-Amiloide/genética , Astrócitos/metabolismo , Encéfalo/metabolismo , Neuroproteção/genética , Proteínas tau/genética , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Precursor de Proteína beta-Amiloide/metabolismo , Animais , Astrócitos/citologia , Encéfalo/patologia , Modelos Animais de Doenças , Feminino , Perfilação da Expressão Gênica , Regulação da Expressão Gênica , Homozigoto , Humanos , Camundongos , Camundongos Transgênicos , Fator 2 Relacionado a NF-E2/genética , Fator 2 Relacionado a NF-E2/metabolismo , Fenótipo , Fosforilação , Proteostase/genética , Proteínas Proto-Oncogênicas/genética , Proteínas Proto-Oncogênicas/metabolismo , Transdução de Sinais , Transativadores/genética , Transativadores/metabolismo , Proteínas tau/metabolismoRESUMO
BACKGROUND: Chronic cerebral hypoperfusion causes damage to the brain's white matter underpinning vascular cognitive impairment. Inflammation and oxidative stress have been proposed as key pathophysiological mechanisms of which the transcription factor Nrf2 is a master regulator. We hypothesised that white matter pathology, microgliosis, blood-brain barrier breakdown and behavioural deficits induced by chronic hypoperfusion would be exacerbated in mice deficient in the transcription factor Nrf2. METHODS: Mice deficient in Nrf2 (male heterozygote or homozygous for Nrf2 knockout) or wild-type littermates on a C57Bl6/J background underwent bilateral carotid artery stenosis (BCAS) to induce chronic cerebral hypoperfusion or sham surgery and survived for a further 6 weeks. White matter pathology was assessed with MAG immunohistochemistry as a marker of altered axon-glial integrity; alterations to astrocytes and microglia/macrophages were assessed with GFAP and Iba1 immunohistochemistry, and blood-brain barrier breakdown was assessed with IgG immunohistochemistry. Behavioural alterations were assessed using 8-arm radial arm maze, and alterations to Nrf2-related and inflammatory-related genes were assessed with qRT-PCR. RESULTS: Chronic cerebral hypoperfusion induced white matter pathology, elevated microglial/macrophage levels and blood-brain barrier breakdown in white matter tracts that were increased in Nrf2+/- mice and further exacerbated by the complete absence of Nrf2. Chronic hypoperfusion induced white matter astrogliosis and induced an impairment in behaviour assessed with radial arm maze; however, these measures were not affected by Nrf2 deficiency. Although Nrf2-related antioxidant gene expression was not altered by chronic cerebral hypoperfusion, there was evidence for elevated pro-inflammatory related gene expression following chronic hypoperfusion that was not affected by Nrf2 deficiency. CONCLUSIONS: The results demonstrate that the absence of Nrf2 exacerbates white matter pathology and microgliosis following cerebral hypoperfusion but does not affect behavioural impairment.
Assuntos
Encéfalo/patologia , Disfunção Cognitiva/metabolismo , Microglia/patologia , Fator 2 Relacionado a NF-E2/deficiência , Substância Branca/patologia , Animais , Isquemia Encefálica/etiologia , Isquemia Encefálica/metabolismo , Isquemia Encefálica/patologia , Estenose das Carótidas/complicações , Disfunção Cognitiva/etiologia , Disfunção Cognitiva/patologia , Modelos Animais de Doenças , Macrófagos/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos KnockoutRESUMO
This scientific commentary refers to 'Structural brain networks and functional motor outcome after stroke -a prospective cohort study', by Schlemm et al. (https://doi.org/10.1093/braincomms/fcaa001) in Brain Communications and 'Brain responsivity provides an individual readout for motor recovery after stroke' by Tscherpel et al. (https://doi.org/10.1093/brain/awaa127) in Brain.
RESUMO
Assessment of outcome in preclinical studies of vascular cognitive impairment (VCI) is heterogenous. Through an ARUK Scottish Network supported questionnaire and workshop (mostly UK-based researchers), we aimed to determine underlying variability and what could be implemented to overcome identified challenges. Twelve UK VCI research centres were identified and invited to complete a questionnaire and attend a one-day workshop. Questionnaire responses demonstrated agreement that outcome assessments in VCI preclinical research vary by group and even those common across groups, may be performed differently. From the workshop, six themes were discussed: issues with preclinical models, reasons for choosing functional assessments, issues in interpretation of functional assessments, describing and reporting functional outcome assessments, sharing resources and expertise, and standardization of outcomes. Eight consensus points emerged demonstrating broadly that the chosen assessment should reflect the deficit being measured, and therefore that one assessment does not suit all models; guidance/standardisation on recording VCI outcome reporting is needed and that uniformity would be aided by a platform to share expertise, material, protocols and procedures thus reducing heterogeneity and so increasing potential for collaboration, comparison and replication. As a result of the workshop, UK wide consensus statements were agreed and future priorities for preclinical research identified.
Assuntos
Demência Vascular , Modelos Animais de Doenças , Projetos de Pesquisa/normas , Animais , Consenso , Recuperação de Função Fisiológica , Inquéritos e Questionários , Reino UnidoRESUMO
Forebrain neurons have relatively weak intrinsic antioxidant defenses compared to astrocytes, in part due to hypo-expression of Nrf2, an oxidative stress-induced master regulator of antioxidant and detoxification genes. Nevertheless, neurons do possess the capacity to auto-regulate their antioxidant defenses in response to electrical activity. Activity-dependent Ca2+ signals control the expression of several antioxidant genes, boosting redox buffering capacity, thus meeting the elevated antioxidant requirements associated with metabolically expensive electrical activity. These genes include examples which are reported Nrf2 target genes and yet are induced in a Nrf2-independent manner. Here we discuss the implications for Nrf2 hypofunction in neurons and the mechanisms underlying the Nrf2-independent induction of antioxidant genes by electrical activity. A significant proportion of Nrf2 target genes, defined as those genes controlled by Nrf2 in astrocytes, are regulated by activity-dependent Ca2+ signals in human stem cell-derived neurons. We propose that neurons interpret Ca2+ signals in a similar way to other cell types sense redox imbalance, to broadly induce antioxidant and detoxification genes.
Assuntos
Antioxidantes/metabolismo , Neurônios/metabolismo , Neurônios/fisiologia , Animais , Sinalização do Cálcio/genética , Humanos , Fator 2 Relacionado a NF-E2/genética , Oxirredução , Transdução de Sinais/genéticaRESUMO
Mouse models have shown that cerebral hypoperfusion causes white matter disruption and memory impairment relevant to the study of vascular cognitive impairment and dementia. The associated mechanisms include inflammation and oxidative stress are proposed to drive disruption of myelinated axons within hypoperfused white matter. The aim of this study was to determine if increased endogenous anti-oxidant and anti-inflammatory signalling in astrocytes was protective in a model of mild cerebral hypoperfusion. Transgenically altered mice overexpressing the transcription factor Nrf2 (GFAP-Nrf2) and wild type littermates were subjected to bilateral carotid artery stenosis or sham surgery. Behavioural alterations were assessed using the radial arm maze and tissue was collected for pathology and transcriptome analysis six weeks post-surgery. GFAP-Nrf2 mice showed less pronounced behavioural impairments compared to wild types following hypoperfusion, paralleled by reduced optic tract white matter disruption and astrogliosis. There was no effect of hypoperfusion on anti-oxidant gene alterations albeit the levels were increased in GFAP-Nrf2 mice. Instead, pro-inflammatory gene expression was determined to be significantly upregulated in the optic tract of hypoperfused wild type mice but differentially affected in GFAP-Nrf2 mice. In particular, complement components (C4 and C1q) were increased in wild type hypoperfused mice but expressed at levels similar to controls in hypoperfused GFAP-Nrf2 mice. This study provides evidence that overexpression of Nrf2 in astrocytes exerts beneficial effects through repression of inflammation and supports the potential use of Nrf2-activators in the amelioration of cerebrovascular-related inflammation and white matter degeneration.
Assuntos
Astrócitos/metabolismo , Transtornos Cerebrovasculares/fisiopatologia , Fator 2 Relacionado a NF-E2/genética , Trato Óptico/patologia , Sistema y+ de Transporte de Aminoácidos/genética , Animais , Comportamento Animal , Estenose das Carótidas/patologia , Circulação Cerebrovascular , Transtornos Cerebrovasculares/genética , Disfunção Cognitiva/genética , Disfunção Cognitiva/patologia , Modelos Animais de Doenças , Expressão Gênica , Glutamato-Cisteína Ligase/genética , Aprendizagem em Labirinto , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Fator 2 Relacionado a NF-E2/metabolismo , Substância Branca/patologiaRESUMO
Cerebral small vessel disease (SVD) is a major contributor to stroke, cognitive impairment and dementia with limited therapeutic interventions. There is a critical need to provide mechanistic insight and improve translation between pre-clinical research and the clinic. A 2-day workshop was held which brought together experts from several disciplines in cerebrovascular disease, dementia and cardiovascular biology, to highlight current advances in these fields, explore synergies and scope for development. These proceedings provide a summary of key talks at the workshop with a particular focus on animal models of cerebral vascular disease and dementia, mechanisms and approaches to improve translation. The outcomes of discussion groups on related themes to identify the gaps in knowledge and requirements to advance knowledge are summarized.
Assuntos
Doenças de Pequenos Vasos Cerebrais/etiologia , Pesquisa Translacional Biomédica , Animais , HumanosRESUMO
The brain's white matter is highly vulnerable to reductions in cerebral blood flow via mechanisms that may involve elevated microgliosis and pro-inflammatory pathways. In the present study, the effects of severe cerebral hypoperfusion were investigated on white matter function and inflammation. Male C57Bl/6J mice underwent bilateral common carotid artery stenosis and white matter function was assessed at seven days with electrophysiology in response to evoked compound action potentials (CAPs) in the corpus callosum. The peak latency of CAPs and axonal refractoriness was increased following hypoperfusion, indicating a marked functional impairment in white matter, which was paralleled by axonal and myelin pathology and increased density and numbers of microglia/macrophages. The functional impairment in peak latency was significantly correlated with increased microglia/macrophages. Dimethyl fumarate (DMF; 100 mg/kg), a drug with anti-inflammatory properties, was found to reduce peak latency but not axonal refractoriness. DMF had no effect on hypoperfusion-induced axonal and myelin pathology. The density of microglia/macrophages was significantly increased in vehicle-treated hypoperfused mice, whereas DMF-treated hypoperfused mice had similar levels to that of sham-treated mice. The study suggests that increased microglia/macrophages following cerebral hypoperfusion contributes to the functional impairment in white matter that may be amenable to modulation by DMF.
Assuntos
Transtornos Cerebrovasculares/tratamento farmacológico , Fumarato de Dimetilo/uso terapêutico , Imunossupressores/uso terapêutico , Inflamação/tratamento farmacológico , Microglia/efeitos dos fármacos , Substância Branca/irrigação sanguínea , Animais , Circulação Cerebrovascular/efeitos dos fármacos , Transtornos Cerebrovasculares/imunologia , Transtornos Cerebrovasculares/patologia , Inflamação/imunologia , Inflamação/patologia , Mediadores da Inflamação/imunologia , Masculino , Camundongos Endogâmicos C57BL , Microglia/imunologia , Microglia/patologia , Substância Branca/imunologia , Substância Branca/patologiaRESUMO
BACKGROUND: Transcatheter aortic valve replacement (TAVR) is an increasingly available therapy for the management of aortic stenosis in higher risk populations. Beyond addressing the procedural challenges, centers must attend to the unique requirements of developing TAVR programs from referral to follow-up. AIM: The aim of this article is to outline the recommendations for best practice for program development from centers with early and extensive experience. RECOMMENDATIONS: The guideline-recommended Heart Team approach requires interdisciplinary agreements, delineation of roles and responsibilities, and the development of the role of the TAVR Coordinator. To support appropriate case selection, the screening and evaluation must be organized in a comprehensive clinic visit. In addition to the multimodality imaging tests, the assessment of functional status and frailty is pivotal to the eligibility decision. Throughout the TAVR trajectory, careful attention must be afforded to the integration of geriatric best practices. Pre-procedure care requires patient and family education to manage expectations and facilitate early discharge planning. Peri-procedural care planning, including equipment requirements, monitoring protocols, and emergency intervention agreements, contributes to procedural success. The aims of post-procedure care are to monitor the recovery, facilitate the rapid return to baseline status, and optimize length of stay. TAVR programs require data management strategies to facilitate and monitor program growth, support program evaluation, and meet the requirements for submission to national registries. CONCLUSION: TAVR represents a paradigm shift in the management of structural heart disease. Programmatic success and patient outcomes depend on the development of a comprehensive and collaborative program tailored to TAVR.
Assuntos
Estenose da Valva Aórtica/terapia , Benchmarking/normas , Cateterismo Cardíaco/normas , Implante de Prótese de Valva Cardíaca/normas , Estenose da Valva Aórtica/diagnóstico , Cateterismo Cardíaco/efeitos adversos , Cateterismo Cardíaco/instrumentação , Comportamento Cooperativo , Diagnóstico por Imagem/normas , Definição da Elegibilidade/normas , Implante de Prótese de Valva Cardíaca/efeitos adversos , Implante de Prótese de Valva Cardíaca/instrumentação , Humanos , Comunicação Interdisciplinar , Equipe de Assistência ao Paciente/normas , Valor Preditivo dos Testes , Desenvolvimento de Programas/normas , Indicadores de Qualidade em Assistência à Saúde/normas , Resultado do TratamentoRESUMO
Chronic cerebral hypoperfusion, a sustained modest reduction in cerebral blood flow, is associated with damage to myelinated axons and cognitive decline with ageing. Oligodendrocytes (the myelin producing cells) and their precursor cells (OPCs) may be vulnerable to the effects of hypoperfusion and in some forms of injury OPCs have the potential to respond and repair damage by increased proliferation and differentiation. Using a mouse model of cerebral hypoperfusion we have characterised the acute and long term responses of oligodendrocytes and OPCs to hypoperfusion in the corpus callosum. Following 3 days of hypoperfusion, numbers of OPCs and mature oligodendrocytes were significantly decreased compared to controls. However following 1 month of hypoperfusion, the OPC pool was restored and increased numbers of oligodendrocytes were observed. Assessment of proliferation using PCNA showed no significant differences between groups at either time point but showed reduced numbers of proliferating oligodendroglia at 3 days consistent with the loss of OPCs. Cumulative BrdU labelling experiments revealed higher numbers of proliferating cells in hypoperfused animals compared to controls and showed a proportion of these newly generated cells had differentiated into oligodendrocytes in a subset of animals. Expression of GPR17, a receptor important for the regulation of OPC differentiation following injury, was decreased following short term hypoperfusion. Despite changes to oligodendrocyte numbers there were no changes to the myelin sheath as revealed by ultrastructural assessment and fluoromyelin however axon-glial integrity was disrupted after both 3 days and 1 month hypoperfusion. Taken together, our results demonstrate the initial vulnerability of oligodendroglial pools to modest reductions in blood flow and highlight the regenerative capacity of these cells.
Assuntos
Isquemia Encefálica/fisiopatologia , Corpo Caloso/irrigação sanguínea , Modelos Animais de Doenças , Oligodendroglia/patologia , Animais , Antígenos/metabolismo , Axônios/metabolismo , Axônios/ultraestrutura , Western Blotting , Contagem de Células , Diferenciação Celular , Proliferação de Células , Circulação Cerebrovascular , Doença Crônica , Imuno-Histoquímica , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Microscopia Confocal , Proteína Básica da Mielina/metabolismo , Bainha de Mielina/metabolismo , Bainha de Mielina/ultraestrutura , Proteínas do Tecido Nervoso/metabolismo , Células-Tronco Neurais/metabolismo , Células-Tronco Neurais/patologia , Neuroglia/metabolismo , Neuroglia/ultraestrutura , Oligodendroglia/metabolismo , Antígeno Nuclear de Célula em Proliferação/metabolismo , Proteoglicanas/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Fatores de TempoRESUMO
It is currently unclear whether the GluN2 subtype influences NMDA receptor (NMDAR) excitotoxicity. We report that the toxicity of NMDAR-mediated Ca(2+) influx is differentially controlled by the cytoplasmic C-terminal domains of GluN2B (CTD(2B)) and GluN2A (CTD(2A)). Studying the effects of acute expression of GluN2A/2B-based chimeric subunits with reciprocal exchanges of their CTDs revealed that CTD(2B) enhances NMDAR toxicity, compared to CTD(2A). Furthermore, the vulnerability of forebrain neurons in vitro and in vivo to NMDAR-dependent Ca(2+) influx is lowered by replacing the CTD of GluN2B with that of GluN2A by targeted exon exchange in a mouse knockin model. Mechanistically, CTD(2B) exhibits stronger physical/functional coupling to the PSD-95-nNOS pathway, which suppresses protective CREB activation. Dependence of NMDAR excitotoxicity on the GluN2 CTD subtype can be overcome by inducing high levels of NMDAR activity. Thus, the identity (2A versus 2B) of the GluN2 CTD controls the toxicity dose-response to episodes of NMDAR activity.
Assuntos
N-Metilaspartato/farmacologia , Neurônios/efeitos dos fármacos , Neurônios/fisiologia , Neurotoxinas/farmacologia , Receptores de N-Metil-D-Aspartato/metabolismo , Animais , Cálcio/metabolismo , Células Cultivadas , Proteína 4 Homóloga a Disks-Large , Maleato de Dizocilpina/farmacologia , Relação Dose-Resposta a Droga , Estimulação Elétrica , Embrião de Mamíferos , Proteína Glial Fibrilar Ácida/metabolismo , Proteínas de Fluorescência Verde/genética , Guanilato Quinases/metabolismo , Hipocampo/citologia , Potenciais da Membrana/efeitos dos fármacos , Potenciais da Membrana/genética , Proteínas de Membrana/metabolismo , Camundongos , Camundongos Transgênicos , Modelos Biológicos , Técnicas de Patch-Clamp , Estrutura Terciária de Proteína/genética , Estrutura Terciária de Proteína/fisiologia , Ratos , Receptores de N-Metil-D-Aspartato/genética , TransfecçãoRESUMO
Prophylactic pharmacological activation of astrocytic gene expression driven by the transcription factor Nrf2 boosts antioxidant defences and protects against neuronal loss in ischemia and other disease models. However, the role of Nrf2 in mediating endogenous neuroprotective responses is less clear. We recently showed that Nrf2 is activated by mild oxidative stress in both rodent and human astrocytes. Moreover, brief exposure to ischemic conditions was found to activate Nrf2 both in vivo and in vitro, and this was found to contribute to neuroprotective ischemic preconditioning. Here we show that transient ischemic conditions in vitro and in vivo cause an increase in the expression of Nrf2 target genes associated with the glutathione pathway, including those involved in glutathione biosynthesis and cystine uptake. Taken together, these studies indicate that astrocytic Nrf2 may represent an important mediator of endogenous neuroprotective preconditioning pathways.
Assuntos
Glutationa/metabolismo , Precondicionamento Isquêmico , Fator 2 Relacionado a NF-E2/metabolismo , Transdução de Sinais/fisiologia , Animais , Células Cultivadas , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Fator 2 Relacionado a NF-E2/genética , Reação em Cadeia da Polimerase em Tempo RealRESUMO
Vascular risk factors play a critical role in the development of cognitive decline and AD (Alzheimer's disease), during aging, and often result in chronic cerebral hypoperfusion. The neurobiological link between hypoperfusion and cognitive decline is not yet defined, but is proposed to involve damage to the brain's white matter. In a newly developed mouse model, hypoperfusion, in isolation, produces a slowly developing and diffuse damage to myelinated axons, which is widespread in the brain, and is associated with a selective impairment in working memory. Cerebral hypoperfusion, an early event in AD, has also been shown to be associated with white matter damage and notably an accumulation of amyloid. The present review highlights some of the published data linking white matter disruption to aging and AD as a result of vascular dysfunction. A model is proposed by which chronic cerebral hypoperfusion, as a result of vascular factors, results in both the generation and accumulation of amyloid and injury to white matter integrity, resulting in cognitive impairment. The generation of amyloid and accumulation in the vasculature may act to perpetuate further vascular dysfunction and accelerate white matter pathology, and as a consequence grey matter pathology and cognitive decline.
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Doença de Alzheimer/complicações , Encéfalo/irrigação sanguínea , Modelos Animais de Doenças , Doenças Vasculares/complicações , Doença de Alzheimer/metabolismo , Animais , Encéfalo/metabolismo , Encéfalo/patologia , Humanos , Camundongos , Camundongos Transgênicos , Placa Amiloide/metabolismo , Doenças Vasculares/metabolismoRESUMO
OBJECTIVE: To evaluate literature reporting on the role of norepinephrine in alcohol withdrawal and to determine the safety and efficacy of α(2)-agonists in reducing symptoms of this severe condition. DATA SOURCES: Articles evaluating the efficacy and safety of the α(2)-agonists clonidine and dexmedetomidine were identified from an English-language MEDLINE search (1966-December 2010). Key words included alcohol withdrawal, delirium tremens, clonidine, dexmedetomidine, α(2)-agonist, norepinephrine, and sympathetic overdrive. STUDY SELECTION AND DATA EXTRACTION: Studies that focused on the safety and efficacy of clonidine and dexmedetomidine in both animals and humans were selected. DATA SYNTHESIS: The noradrenergic system, specifically sympathetic overdrive during alcohol withdrawal, may play an important role in withdrawal symptom development. Symptoms of sympathetic overdrive include anxiety, agitation, elevated blood pressure, tachycardia, and tremor. Therefore, α(2)-agonists, which decrease norepinephine release, may have a role in reducing alcohol withdrawal symptoms. The majority of controlled animal and human studies evaluated clonidine, but the most recent literature is from case reports on dexmedetomidine. The literature reviewed here demonstrate that these 2 α(2)-agonists safely and effectively reduce symptoms of sympathetic overdrive and concomitant medication use. Dexmedetomidine may offer an advantage over current sedative medications used in the intensive care unit, such as not requiring intubation with its use, and therefore further study is needed to fully elicit its benefit in alcohol withdrawal. CONCLUSION: Clonidine and dexmedetomidine may provide additional benefit in managing alcohol withdrawal by offering a different mechanism of action for targeting withdrawal symptoms. Based on literature reviewed here, the primary role for clonidine and dexmedetomidine is as adjunctive treatment to benzodiazepines, the standard of care in alcohol withdrawal.
Assuntos
Agonistas de Receptores Adrenérgicos alfa 2/farmacologia , Clonidina/farmacologia , Dexmedetomidina/farmacologia , Etanol/efeitos adversos , Síndrome de Abstinência a Substâncias/tratamento farmacológico , Agonistas de Receptores Adrenérgicos alfa 2/efeitos adversos , Animais , Clonidina/efeitos adversos , Dexmedetomidina/efeitos adversos , Humanos , Norepinefrina/metabolismo , Síndrome de Abstinência a Substâncias/metabolismoAssuntos
Astrócitos/metabolismo , Regulação Enzimológica da Expressão Gênica/fisiologia , Fator 2 Relacionado a NF-E2/metabolismo , Neurônios/metabolismo , Fármacos Neuroprotetores/metabolismo , Estresse Oxidativo/fisiologia , Animais , Células Cultivadas , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Heme Oxigenase (Desciclizante)/metabolismo , Peróxido de Hidrogênio/farmacologia , Precondicionamento Isquêmico , Oxirredutases atuantes sobre Doadores de Grupo Enxofre/metabolismo , RatosRESUMO
The integrity of the white matter is critical in regulating efficient neuronal communication and maintaining cognitive function. Damage to brain white matter putatively contributes to age-related cognitive decline. There is a growing interest in animal models from which the mechanistic basis of white matter pathology in aging can be elucidated but to date there has been a lack of systematic behavior and pathology in the same mice. Anatomically widespread, diffuse white matter damage was induced, in 3 different cohorts of C57Bl/6J mice, by chronic hypoperfusion produced by bilateral carotid stenosis. A comprehensive assessment of spatial memory (spatial reference learning and memory; cohort 1) and serial spatial learning and memory (cohort 2) using the water maze, and spatial working memory (cohort 3) using the 8-arm radial arm maze, was conducted. In parallel, a systematic assessment of white matter components (myelin, axon, glia) was conducted using immunohistochemical markers (myelin-associated glycoprotein [MAG], degraded myelin basic protein [dMBP], anti-amyloid precursor protein [APP], anti-ionized calcium-binding adapter molecule [Iba-1]). Ischemic neuronal perikarya damage, assessed using histology (hematoxylin and eosin; H&E), was absent in all shams but was present in some hypoperfused mice (2/11 in cohort 1, 4/14 in cohort 2, and 17/24 in cohort 3). All animals with neuronal perikaryal damage were excluded from further study. Diffuse white matter damage occurred, throughout the brain, in all hypoperfused mice in each cohort and was essentially absent in sham-operated controls. There was a selective impairment in spatial working memory, with all other measures of spatial memory remaining intact, in hypoperfused mice with selective white matter damage. The results demonstrate that diffuse white matter pathology, in the absence of gray matter damage, induces a selective impairment of spatial working memory. This highlights the importance of assessing parallel pathology and behavior in the same mice.
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Transtornos da Memória/patologia , Memória de Curto Prazo/fisiologia , Fibras Nervosas Mielinizadas/patologia , Comportamento Espacial/fisiologia , Animais , Masculino , Aprendizagem em Labirinto/fisiologia , Transtornos da Memória/etiologia , Camundongos , Camundongos Endogâmicos C57BL , Desempenho Psicomotor/fisiologiaRESUMO
Mild traumatic brain injury (TBI) accounts for up to 80% of clinical TBI and can result in cognitive impairment and white matter damage that may develop and persist over several years. Clinically relevant models of mild TBI for investigation of neurobiological changes and the development of therapeutic strategies are poorly developed. In this study we investigated the temporal profile of axonal and somal injury that may contribute to cognitive impairments in a mouse model of mild TBI. Neuronal perikaryal damage (hematoxylin and eosin and Fluoro-Jade C), myelin integrity (myelin basic protein and myelin-associated glycoprotein), and axonal damage (amyloid precursor protein), were evaluated by immunohistochemistry at 4 h, 24 h, 72 h, 4 weeks, and 6 weeks after mild lateral fluid percussion brain injury (0.9 atm; righting time 167 +/- 15 sec). At 3 weeks post-injury spatial reference learning and memory were tested in the Morris water maze (MWM). Levels of damage to neuronal cell bodies were comparable in the brain-injured and sham groups. Myelin integrity was minimally altered following injury. Clear alterations in axonal damage were observed at various time points after injury. Axonal damage was localized to the cingulum at 4 h post-injury. At 4 and 6 weeks post-injury, axonal damage was evident in the external capsule, and was seen at 6 weeks in the dorsal thalamic nuclei. At 3 weeks post-injury, injured mice showed an impaired ability to learn the water maze task, suggesting injury-induced alterations in search strategy learning. The evolving localization of axonal damage points to ongoing degeneration after injury that is concomitant with a deficit in learning.
Assuntos
Axônios/patologia , Lesões Encefálicas/patologia , Lesões Encefálicas/psicologia , Transtornos Cognitivos/etiologia , Transtornos Cognitivos/psicologia , Animais , Encéfalo/patologia , Imuno-Histoquímica , Masculino , Aprendizagem em Labirinto/fisiologia , Camundongos , Camundongos Endogâmicos C57BL , Bainha de Mielina/patologia , Neurônios/patologia , Desempenho Psicomotor/fisiologiaRESUMO
OBJECTIVE: To describe the case of a patient with postherpetic neuralgia (PHN) who had a marked response to topiramate despite failure of several previous therapies. CASE SUMMARY: A 79-year-old white male with multiple medical comorbidities developed severe trigeminal territory PHN requiring treatment with opiates to maintain adequate pain relief. Topiramate was initiated after the patient failed treatment with 4 other antiepileptic medications due to various adverse events. After 3 months of topiramate therapy, with dosages up to 50 mg twice daily, PHN pain had decreased to the point that the patient was able to discontinue the use of opiates entirely. At time of writing, he continued to be maintained on topiramate 50 mg twice daily with good pain relief and no reported adverse effects. DISCUSSION: Topiramate exhibits a number of actions that may contribute to the relief of neuropathic pain, including modulation of voltage-gated sodium and calcium channels, potentiation of gamma-aminobutyric acid inhibition, and blockade of alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA)/kainite glutamate receptors. Current evidence-based recommendations consider topiramate to be a third-line agent for the treatment of neuropathic pain based on studies of its use in painful diabetic neuropathy and chronic lumbar radicular pain. A comprehensive search of MEDLINE (1950-August 2008) using the terms postherpetic neuralgia, neuralgia, and topiramate revealed only one previously published case report evaluating the use of topiramate specifically for treatment of PHN. CONCLUSIONS: While it is impossible to determine whether pain relief in this case was due to treatment with topiramate as opposed to spontaneous resolution of pain over time, this additional case report suggests that topiramate may be a useful treatment option for patients with PHN who have not responded to or are intolerant of other interventions. Further studies are needed to determine whether topiramate should receive a stronger recommendation for the treatment of PHN.
Assuntos
Frutose/análogos & derivados , Neuralgia Pós-Herpética/diagnóstico , Neuralgia Pós-Herpética/tratamento farmacológico , Idoso , Frutose/farmacologia , Frutose/uso terapêutico , Humanos , Masculino , Medição da Dor/efeitos dos fármacos , TopiramatoRESUMO
BACKGROUND: Aortic valve replacement (AVR) is the treatment of choice for critical aortic stenosis. Selected patients have not previously been referred for AVR because of excessive risk of mortality and morbidity with surgery. The option of transcatheter aortic valve implantation (TAVI) has increased referral of this high-risk cohort for therapeutic intervention. We report the management and outcomes of these patients. METHODS: Patients referred for TAVI from December 2005 to December 2007 were evaluated and followed up for intermediate-term all cause mortality. Patients received medical management, TAVI, conventional AVR, or balloon valvuloplasty (BAV) based on risk profile, hemodynamic and echocardiographic criteria, physician judgment, or patient choice. Patients were compared for demographics, Society of Thoracic Surgeons predicted risk of mortality score, and outcomes after AVR, TAVI, or BAV. RESULTS: One hundred five patients were referred for TAVI during a 24-month period. Fifty-two patients (49.5%) received medical management, 16 (15.2%) conventional AVR, 21 (20.0%) received TAVI, and 16 (15.2%) received BAV. Patients were classified as medical management because of physician or patient choice, not meeting TAVI criteria, or underevaluation for a possible procedure. For all patients the average length of follow-up was 159 +/- 147 days. Patients receiving BAV had a Society of Thoracic Surgeons predicted risk of mortality score greater than those having medical management, AVR, or TAVI. Thirty-day mortality was 1 of 16 patients (6.3%) for AVR, 2 of 21 patients (9.5%) with TAVI, 2 of 16 patients (12.5%) for BAV, and 7 of 52 patients (13.5%) for the medical management cohort. Overall mortality during follow-up was 42.3% (22 of 52 patients) for medical management, 19.1% (4 of 21 patients) for TAVI, 12.5% (2 of 16 patients) for AVR, and 37.5% (6 of 16 patients) for BAV. CONCLUSIONS: The population of patients screened for transcatheter therapy is complex and heterogeneous. Medical management alone demonstrates a high mortality rate, and BAV, although providing transient symptomatic relief, does not favorably impact survival. The majority of referred patients (65.7%), including those that declined intervention, were candidates for some form of valve replacement therapy, either TAVI or AVR. Transcatheter aortic valve implantation can be performed in appropriately selected patients with good early and immediate-term outcomes.