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1.
Cell ; 174(3): 521-535.e13, 2018 07 26.
Artigo em Inglês | MEDLINE | ID: mdl-30033363

RESUMO

Many human spinal cord injuries are anatomically incomplete but exhibit complete paralysis. It is unknown why spared axons fail to mediate functional recovery in these cases. To investigate this, we undertook a small-molecule screen in mice with staggered bilateral hemisections in which the lumbar spinal cord is deprived of all direct brain-derived innervation, but dormant relay circuits remain. We discovered that a KCC2 agonist restored stepping ability, which could be mimicked by selective expression of KCC2, or hyperpolarizing DREADDs, in the inhibitory interneurons between and around the staggered spinal lesions. Mechanistically, these treatments transformed this injury-induced dysfunctional spinal circuit to a functional state, facilitating the relay of brain-derived commands toward the lumbar spinal cord. Thus, our results identify spinal inhibitory interneurons as a roadblock limiting the integration of descending inputs into relay circuits after injury and suggest KCC2 agonists as promising treatments for promoting functional recovery after spinal cord injury.


Assuntos
Traumatismos da Medula Espinal/tratamento farmacológico , Simportadores/agonistas , Simportadores/metabolismo , Animais , Axônios , Regulação da Expressão Gênica/genética , Interneurônios/fisiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Regeneração Nervosa/fisiologia , Plasticidade Neuronal/genética , Neurônios/metabolismo , Recuperação de Função Fisiológica/genética , Recuperação de Função Fisiológica/fisiologia , Medula Espinal , Simportadores/uso terapêutico , Cotransportadores de K e Cl-
3.
Proc Natl Acad Sci U S A ; 121(15): e2314763121, 2024 Apr 09.
Artigo em Inglês | MEDLINE | ID: mdl-38557194

RESUMO

Although sudden sensorineural hearing loss (SSNHL) is a serious condition, there are currently no approved drugs for its treatment. Nevertheless, there is a growing understanding that the cochlear pathologies that underlie SSNHL include apoptotic death of sensory outer hair cells (OHCs) as well as loss of ribbon synapses connecting sensory inner hair cells (IHCs) and neurites of the auditory nerve, designated synaptopathy. Noise-induced hearing loss (NIHL) is a common subtype of SSNHL and is widely used to model hearing loss preclinically. Here, we demonstrate that a single interventive application of a small pyridoindole molecule (AC102) into the middle ear restored auditory function almost to prenoise levels in a guinea pig model of NIHL. AC102 prevented noise-triggered loss of OHCs and reduced IHC synaptopathy suggesting a role of AC102 in reconnecting auditory neurons to their sensory target cells. Notably, AC102 exerted its therapeutic properties over a wide frequency range. Such strong improvements in hearing have not previously been demonstrated for other therapeutic agents. In vitro experiments of a neuronal damage model revealed that AC102 protected cells from apoptosis and promoted neurite growth. These effects may be explained by increased production of adenosine triphosphate, indicating improved mitochondrial function, and reduced levels of reactive-oxygen species which prevents the apoptotic processes responsible for OHC death. This action profile of AC102 might be causal for the observed hearing recovery in in vivo models.


Assuntos
Perda Auditiva Provocada por Ruído , Perda Auditiva Neurossensorial , Cobaias , Animais , Audição , Cóclea , Ruído/efeitos adversos , Células Ciliadas Auditivas Externas/fisiologia , Limiar Auditivo
4.
Nature ; 588(7836): 124-129, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-33268865

RESUMO

Ageing is a degenerative process that leads to tissue dysfunction and death. A proposed cause of ageing is the accumulation of epigenetic noise that disrupts gene expression patterns, leading to decreases in tissue function and regenerative capacity1-3. Changes to DNA methylation patterns over time form the basis of ageing clocks4, but whether older individuals retain the information needed to restore these patterns-and, if so, whether this could improve tissue function-is not known. Over time, the central nervous system (CNS) loses function and regenerative capacity5-7. Using the eye as a model CNS tissue, here we show that ectopic expression of Oct4 (also known as Pou5f1), Sox2 and Klf4 genes (OSK) in mouse retinal ganglion cells restores youthful DNA methylation patterns and transcriptomes, promotes axon regeneration after injury, and reverses vision loss in a mouse model of glaucoma and in aged mice. The beneficial effects of OSK-induced reprogramming in axon regeneration and vision require the DNA demethylases TET1 and TET2. These data indicate that mammalian tissues retain a record of youthful epigenetic information-encoded in part by DNA methylation-that can be accessed to improve tissue function and promote regeneration in vivo.


Assuntos
Envelhecimento/genética , Reprogramação Celular/genética , Metilação de DNA , Epigênese Genética , Olho , Regeneração Nervosa/genética , Visão Ocular/genética , Visão Ocular/fisiologia , Envelhecimento/fisiologia , Animais , Axônios/fisiologia , Linhagem Celular Tumoral , Sobrevivência Celular , Proteínas de Ligação a DNA/genética , Dependovirus/genética , Dioxigenases , Modelos Animais de Doenças , Olho/citologia , Olho/inervação , Olho/patologia , Feminino , Vetores Genéticos/genética , Glaucoma/genética , Glaucoma/patologia , Humanos , Fator 4 Semelhante a Kruppel , Fatores de Transcrição Kruppel-Like/genética , Camundongos , Camundongos Endogâmicos C57BL , Fator 3 de Transcrição de Octâmero/genética , Traumatismos do Nervo Óptico/genética , Proteínas Proto-Oncogênicas/genética , Células Ganglionares da Retina/citologia , Fatores de Transcrição SOXB1/genética , Transcriptoma/genética
5.
Brain ; 146(8): 3500-3512, 2023 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-37370200

RESUMO

Infections are prevalent after spinal cord injury (SCI), constitute the main cause of death and are a rehabilitation confounder associated with impaired recovery. We hypothesize that SCI causes an acquired lesion-dependent (neurogenic) immune suppression as an underlying mechanism to facilitate infections. The international prospective multicentre cohort study (SCIentinel; protocol registration DRKS00000122; n = 111 patients) was designed to distinguish neurogenic from general trauma-related effects on the immune system. Therefore, SCI patient groups differing by neurological level, i.e. high SCI [thoracic (Th)4 or higher]; low SCI (Th5 or lower) and severity (complete SCI; incomplete SCI), were compared with a reference group of vertebral fracture (VF) patients without SCI. The primary outcome was quantitative monocytic Human Leukocyte Antigen-DR expression (mHLA-DR, synonym MHC II), a validated marker for immune suppression in critically ill patients associated with infection susceptibility. mHLA-DR was assessed from Day 1 to 10 weeks after injury by applying standardized flow cytometry procedures. Secondary outcomes were leucocyte subpopulation counts, serum immunoglobulin levels and clinically defined infections. Linear mixed models with multiple imputation were applied to evaluate group differences of logarithmic-transformed parameters. Mean quantitative mHLA-DR [ln (antibodies/cell)] levels at the primary end point 84 h after injury indicated an immune suppressive state below the normative values of 9.62 in all groups, which further differed in its dimension by neurological level: high SCI [8.95 (98.3% confidence interval, CI: 8.63; 9.26), n = 41], low SCI [9.05 (98.3% CI: 8.73; 9.36), n = 29], and VF without SCI [9.25 (98.3% CI: 8.97; 9.53), n = 41, P = 0.003]. Post hoc analysis accounting for SCI severity revealed the strongest mHLA-DR decrease [8.79 (95% CI: 8.50; 9.08)] in the complete, high SCI group, further demonstrating delayed mHLA-DR recovery [9.08 (95% CI: 8.82; 9.38)] and showing a difference from the VF controls of -0.43 (95% CI: -0.66; -0.20) at 14 days. Complete, high SCI patients also revealed constantly lower serum immunoglobulin G [-0.27 (95% CI: -0.45; -0.10)] and immunoglobulin A [-0.25 (95% CI: -0.49; -0.01)] levels [ln (g/l × 1000)] up to 10 weeks after injury. Low mHLA-DR levels in the range of borderline immunoparalysis (below 9.21) were positively associated with the occurrence and earlier onset of infections, which is consistent with results from studies on stroke or major surgery. Spinal cord injured patients can acquire a secondary, neurogenic immune deficiency syndrome characterized by reduced mHLA-DR expression and relative hypogammaglobulinaemia (combined cellular and humoral immune deficiency). mHLA-DR expression provides a basis to stratify infection-risk in patients with SCI.


Assuntos
Antígenos HLA-DR , Traumatismos da Medula Espinal , Humanos , Estudos de Coortes , Estudos Prospectivos , Traumatismos da Medula Espinal/complicações , Síndrome , Monócitos
6.
Glia ; 67(4): 703-717, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30485542

RESUMO

Clostridium botulinum C3 transferase (C3bot) ADP-ribosylates rho proteins to change cellular functions in a variety of cell types including astrocytes and neurons. The intermediate filament protein vimentin as well as transmembrane integrins are involved in internalization of C3bot into cells. The exact contribution, however, of these proteins to binding of C3bot to the cell surface and subsequent cellular uptake remains to be unraveled. By comparing primary astrocyte cultures derived from wild-type with Vim-/- mice, we demonstrate that astrocytes lacking vimentin exhibited a delayed ADP-ribosylation of rhoA concurrent with a blunted morphological response. This functional impairment was rescued by the extracellular excess of recombinant vimentin. Binding assays using C3bot harboring a mutated integrin-binding RGD motif (C3bot-G89I) revealed the involvement of integrins in astrocyte binding of C3bot. Axonotrophic effects of C3bot are vimentin dependent and postulate an underlying mechanism entertaining a molecular cross-talk between astrocytes and neurons. We present functional evidence for astrocytic release of vimentin by exosomes using an in vitro scratch wound model. Exosomal vimentin+ particles released from wild-type astrocytes promote the interaction of C3bot with neuronal membranes. This effect vanished when culturing Vim-/- astrocytes. Specificity of these findings was confirmed by recombinant vimentin propagating enhanced binding of C3bot to synaptosomes from rat spinal cord and mouse brain. We hypothesize that vimentin+ exosomes released by reactive astrocytes provide a novel molecular mechanism constituting axonotrophic (neuroprotective) and plasticity augmenting effects of C3bot after spinal cord injury.


Assuntos
ADP Ribose Transferases/farmacologia , Astrócitos/metabolismo , Toxinas Botulínicas/farmacologia , Vesículas Extracelulares/fisiologia , Neurônios/metabolismo , Vimentina/metabolismo , ADP Ribose Transferases/metabolismo , Animais , Astrócitos/ultraestrutura , Toxinas Botulínicas/metabolismo , Células Cultivadas , Modelos Animais de Doenças , Vesículas Extracelulares/ultraestrutura , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Microscopia Imunoeletrônica , Neurônios/efeitos dos fármacos , Neurônios/ultraestrutura , Ligação Proteica/efeitos dos fármacos , Ligação Proteica/genética , Ratos , Ratos Endogâmicos Lew , Medula Espinal/citologia , Traumatismos da Medula Espinal/metabolismo , Traumatismos da Medula Espinal/patologia , Frações Subcelulares/efeitos dos fármacos , Frações Subcelulares/metabolismo , Frações Subcelulares/ultraestrutura , Fatores de Tempo , Vimentina/genética
7.
PLoS Biol ; 14(5): e1002468, 2016 05.
Artigo em Inglês | MEDLINE | ID: mdl-27244556

RESUMO

Olfactory ensheathing cell (OEC) transplantation is a candidate cellular treatment approach for human spinal cord injury (SCI) due to their unique regenerative potential and autologous origin. The objective of this study was, through a meta-epidemiologic approach, (i) to assess the efficacy of OEC transplantation on locomotor recovery after traumatic experimental SCI and (ii) to estimate the likelihood of reporting bias and/or missing data. A study protocol was finalized before data collection. Embedded into a systematic review and meta-analysis, we conducted a literature research of databases including PubMed, EMBASE, and ISI Web of Science from 1949/01 to 2014/10 with no language restrictions, screened by two independent investigators. Studies were included if they assessed neurobehavioral improvement after traumatic experimental SCI, administrated no combined interventions, and reported the number of animals in the treatment and control group. Individual effect sizes were pooled using a random effects model. Details regarding the study design were extracted and impact of these on locomotor outcome was assessed by meta-regression. Missing data (reporting bias) was determined by Egger regression and Funnel-plotting. The primary study outcome assessed was improvement in locomotor function at the final time point of measurement. We included 49 studies (62 experiments, 1,164 animals) in the final analysis. The overall improvement in locomotor function after OEC transplantation, measured using the Basso, Beattie, and Bresnahan (BBB) score, was 20.3% (95% CI 17.8-29.5). One missing study was imputed by trim and fill analysis, suggesting only slight publication bias and reducing the overall effect to a 19.2% improvement of locomotor activity. Dose-response ratio supports neurobiological plausibility. Studies were assessed using a 9-point item quality score, resulting in a median score of 5 (interquartile range [IQR] 3-5). In conclusion, OEC transplantation exerts considerable beneficial effects on neurobehavioral recovery after traumatic experimental SCI. Publication bias was minimal and affirms the translational potential of efficacy, but safety cannot be adequately assessed. The data justify OECs as a cellular substrate to develop and optimize minimally invasive and safe cellular transplantation paradigms for the lesioned spinal cord embedded into state-of-the-art Phase I/II clinical trial design studies for human SCI.


Assuntos
Transplante de Células/métodos , Bulbo Olfatório/citologia , Traumatismos da Medula Espinal/terapia , Animais , Transplante de Células/efeitos adversos , Modelos Animais de Doenças , Bulbo Olfatório/transplante , Viés de Publicação , Resultado do Tratamento
8.
J Neurosci ; 37(48): 11731-11743, 2017 Nov 29.
Artigo em Inglês | MEDLINE | ID: mdl-29109234

RESUMO

Resolution of inflammation is defective after spinal cord injury (SCI), which impairs tissue integrity and remodeling and leads to functional deficits. Effective pharmacological treatments for SCI are not currently available. Maresin 1 (MaR1) is a highly conserved specialized proresolving mediator (SPM) hosting potent anti-inflammatory and proresolving properties with potent tissue regenerative actions. Here, we provide evidence that the inappropriate biosynthesis of SPM in the lesioned spinal cord hampers the resolution of inflammation and leads to deleterious consequences on neurological outcome in adult female mice. We report that, after spinal cord contusion injury in adult female mice, the biosynthesis of SPM is not induced in the lesion site up to 2 weeks after injury. Exogenous administration of MaR1, a highly conserved SPM, propagated inflammatory resolution after SCI, as revealed by accelerated clearance of neutrophils and a reduction in macrophage accumulation at the lesion site. In the search of mechanisms underlying the proresolving actions of MaR1 in SCI, we found that this SPM facilitated several hallmarks of resolution of inflammation, including reduction of proinflammatory cytokines (CXCL1, CXCL2, CCL3, CCL4, IL6, and CSF3), silencing of major inflammatory intracellular signaling cascades (STAT1, STAT3, STAT5, p38, and ERK1/2), redirection of macrophage activation toward a prorepair phenotype, and increase of the phagocytic engulfment of neutrophils by macrophages. Interestingly, MaR1 administration improved locomotor recovery significantly and mitigated secondary injury progression in a clinical relevant model of SCI. These findings suggest that proresolution, immunoresolvent therapies constitute a novel approach to improving neurological recovery after acute SCI.SIGNIFICANCE STATEMENT Inflammation is a protective response to injury or infection. To result in tissue homeostasis, inflammation has to resolve over time. Incomplete or delayed resolution leads to detrimental effects, including propagated tissue damage and impaired wound healing, as occurs after spinal cord injury (SCI). We report that inflammation after SCI is dysregulated in part due to inappropriate synthesis of proresolving lipid mediators. We demonstrate that the administration of the resolution agonist referred to as maresin 1 (MaR1) after SCI actively propagates resolution processes at the lesion site and improves neurological outcome. MaR1 is identified as an interventional candidate to attenuate dysregulated lesional inflammation and to restore functional recovery after SCI.


Assuntos
Anti-Inflamatórios/administração & dosagem , Ácidos Docosa-Hexaenoicos/administração & dosagem , Fármacos Neuroprotetores/administração & dosagem , Recuperação de Função Fisiológica/efeitos dos fármacos , Traumatismos da Medula Espinal/tratamento farmacológico , Animais , Feminino , Locomoção/efeitos dos fármacos , Locomoção/fisiologia , Macrófagos/efeitos dos fármacos , Macrófagos/fisiologia , Camundongos , Camundongos Endogâmicos C57BL , Neutrófilos/efeitos dos fármacos , Neutrófilos/fisiologia , Recuperação de Função Fisiológica/fisiologia , Traumatismos da Medula Espinal/fisiopatologia , Vértebras Torácicas
9.
Brain ; 139(Pt 3): 692-707, 2016 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-26754788

RESUMO

Pneumonia is the leading cause of death after acute spinal cord injury and is associated with poor neurological outcome. In contrast to the current understanding, attributing enhanced infection susceptibility solely to the patient's environment and motor dysfunction, we investigate whether a secondary functional neurogenic immune deficiency (spinal cord injury-induced immune deficiency syndrome, SCI-IDS) may account for the enhanced infection susceptibility. We applied a clinically relevant model of experimental induced pneumonia to investigate whether the systemic SCI-IDS is functional sufficient to cause pneumonia dependent on spinal cord injury lesion level and investigated whether findings are mirrored in a large prospective cohort study after human spinal cord injury. In a mouse model of inducible pneumonia, high thoracic lesions that interrupt sympathetic innervation to major immune organs, but not low thoracic lesions, significantly increased bacterial load in lungs. The ability to clear the bacterial load from the lung remained preserved in sham animals. Propagated immune susceptibility depended on injury of central pre-ganglionic but not peripheral postganglionic sympathetic innervation to the spleen. Thoracic spinal cord injury level was confirmed as an independent increased risk factor of pneumonia in patients after motor complete spinal cord injury (odds ratio = 1.35, P < 0.001) independently from mechanical ventilation and preserved sensory function by multiple regression analysis. We present evidence that spinal cord injury directly causes increased risk for bacterial infection in mice as well as in patients. Besides obvious motor and sensory paralysis, spinal cord injury also induces a functional SCI-IDS ('immune paralysis'), sufficient to propagate clinically relevant infection in an injury level dependent manner.


Assuntos
Síndromes de Imunodeficiência/etiologia , Síndromes de Imunodeficiência/patologia , Traumatismos da Medula Espinal/complicações , Traumatismos da Medula Espinal/patologia , Vértebras Torácicas/lesões , Vértebras Torácicas/patologia , Animais , Suscetibilidade a Doenças , Masculino , Camundongos , Camundongos Endogâmicos C57BL
10.
BMC Neurol ; 16: 170, 2016 Sep 13.
Artigo em Inglês | MEDLINE | ID: mdl-27618987

RESUMO

BACKGROUND: Natural killer (NK) cells comprise the main components of lymphocyte-mediated nonspecific immunity. Through their effector function they play a crucial role combating bacterial and viral challenges. They are also thought to be key contributors to the systemic spinal cord injury-induced immune-deficiency syndrome (SCI-IDS). SCI-IDS increases susceptibility to infection and extends to the post-acute and chronic phases after SCI. METHODS AND DESIGN: The prospective study of NK cell function after traumatic SCI was carried out in two centers in Berlin, Germany. SCI patients and control patients with neurologically silent vertebral fracture also undergoing surgical stabilization were enrolled. Furthermore healthy controls were included to provide reference data. The NK cell function was assessed at 7 (5-9) days, 14 days (11-28) days, and 10 (8-12) weeks post-trauma. Clinical documentation included the American Spinal Injury Association (ASIA) impairment scale (AIS), neurological level of injury, infection status, concomitant injury, and medications. The primary endpoint of the study is CD107a expression by NK cells (cytotoxicity marker) 8-12 weeks following SCI. Secondary endpoints are the NK cell's TNF-α and IFN-γ production by the NK cells 8-12 weeks following SCI. DISCUSSION: The protocol of this study was developed to investigate the hypotheses whether i) SCI impairs NK cell function throughout the post-acute and sub-acute phases after SCI and ii) the degree of impairment relates to lesion height and severity. A deeper understanding of the SCI-IDS is crucial to enable strategies for prevention of infections, which are associated with poor neurological outcome and elevated mortality. TRIAL REGISTRATION: DRKS00009855 .


Assuntos
Células Matadoras Naturais/imunologia , Traumatismos da Medula Espinal/imunologia , Adulto , Biomarcadores , Estudos de Casos e Controles , Células Cultivadas , Protocolos Clínicos , Humanos , Interferon gama/biossíntese , Células Matadoras Naturais/metabolismo , Estudos Longitudinais , Proteína 1 de Membrana Associada ao Lisossomo/biossíntese , Masculino , Estudos Prospectivos , Traumatismos da Medula Espinal/complicações , Fatores de Tempo , Fator de Necrose Tumoral alfa/biossíntese , Adulto Jovem
11.
Proc Natl Acad Sci U S A ; 108(16): 6555-60, 2011 Apr 19.
Artigo em Inglês | MEDLINE | ID: mdl-21467223

RESUMO

Directed cell migration is a prerequisite not only for the development of the central nervous system, but also for topically restricted, appropriate immune responses. This is crucial for host defense and immune surveillance. Attracting environmental cues guiding leukocyte cell traffic are likely to be complemented by repulsive cues, which actively abolish cell migration. One such a paradigm exists in the developing nervous system, where neuronal migration and axonal path finding is balanced by chemoattractive and chemorepulsive cues, such as the neuronal repulsive guidance molecule-A (RGM-A). As expressed at the inflammatory site, the role of RGM-A within the immune response remains unclear. Here we report that RGM-A (i) is expressed by epithelium and leukocytes (granulocytes, monocytes, and T/B lymphocytes); (ii) inhibits leukocyte migration by contact repulsion and chemorepulsion, depending on dosage, through its receptor neogenin; and (iii) suppresses the inflammatory response in a model of zymosan-A-induced peritonitis. Systemic application of RGM-A attenuates the humoral proinflammatory response (TNF-α, IL-6, and macrophage inflammatory protein 1α), infiltration of inflammatory cell traffic, and edema formation. In contrast, the demonstrated anti-inflammatory effect of RGM-A is absent in mice homozygous for a gene trap mutation in the neo1 locus (encoding neogenin). Thus, our results suggest that RGM-A is a unique endogenous inhibitor of leukocyte chemotaxis that limits inflammatory leukocyte traffic and creates opportunities to better understand and treat pathologies caused by exacerbated or misdirected inflammatory responses.


Assuntos
Quimiotaxia/imunologia , Regulação da Expressão Gênica/imunologia , Leucócitos/imunologia , Proteínas do Tecido Nervoso/imunologia , Peritonite/imunologia , Animais , Células CACO-2 , Quimiotaxia/efeitos dos fármacos , Quimiotaxia/genética , Citocinas/biossíntese , Citocinas/genética , Citocinas/imunologia , Epitélio/imunologia , Epitélio/metabolismo , Proteínas Ligadas por GPI/biossíntese , Proteínas Ligadas por GPI/genética , Proteínas Ligadas por GPI/imunologia , Regulação da Expressão Gênica/efeitos dos fármacos , Regulação da Expressão Gênica/genética , Humanos , Inflamação/induzido quimicamente , Inflamação/genética , Inflamação/imunologia , Inflamação/metabolismo , Leucócitos/metabolismo , Camundongos , Camundongos Knockout , Proteínas do Tecido Nervoso/biossíntese , Proteínas do Tecido Nervoso/genética , Especificidade de Órgãos/efeitos dos fármacos , Especificidade de Órgãos/genética , Especificidade de Órgãos/imunologia , Peritonite/induzido quimicamente , Peritonite/genética , Peritonite/metabolismo , Zimosan/toxicidade
12.
BMC Neurol ; 13: 168, 2013 Nov 09.
Artigo em Inglês | MEDLINE | ID: mdl-24206943

RESUMO

BACKGROUND: Infections are the leading cause of death in the acute phase following spinal cord injury and qualify as independent risk factor for poor neurological outcome ("disease modifying factor"). The enhanced susceptibility for infections is not stringently explained by the increased risk of aspiration in tetraplegic patients, neurogenic bladder dysfunction, or by high-dose methylprednisolone treatment. Experimental and clinical pilot data suggest that spinal cord injury disrupts the balanced interplay between the central nervous system and the immune system. The primary hypothesis is that the Spinal Cord Injury-induced Immune Depression Syndrome (SCI-IDS) is 'neurogenic' including deactivation of adaptive and innate immunity with decreased HLA-DR expression on monocytes as a key surrogate parameter. Secondary hypotheses are that the Immune Depression Syndrome is i) injury level- and ii) severity-dependent, iii) triggers transient lymphopenia, and iv) causes qualitative functional leukocyte deficits, which may endure the post-acute phase after spinal cord injury. METHODS/DESIGN: SCIentinel is a prospective, international, multicenter study aiming to recruit about 118 patients with acute spinal cord injury or control patients with acute vertebral fracture without neurological deficits scheduled for spinal surgery. The assessment points are: i) <31 hours, ii) 31-55 hours, iii) 7 days, iv) 14 days, and v) 10 weeks post-trauma. Assessment includes infections, concomitant injury, medication and neurological classification using American Spinal Injury Association impairment scale (AIS) and neurological level. Laboratory analyses comprise haematological profiling, immunophenotyping, including HLA-DR expression on monocytes, cytokines and gene expression of immune modulators. We provide an administrative interim analysis of the recruitment schedule of the trial. DISCUSSION: The objectives are to characterize the dysfunction of the innate and adaptive immune system after spinal cord injury and to explore its proposed 'neurogenic' origin by analyzing its correlation with lesion height and severity. The trial protocol considers difficulties of enrolment in an acute setting, and loss to follow up. The administrative interim analysis confirmed the feasibility of the protocol. Better understanding of the SCI-IDS is crucial to reduce co-morbidities and thereby to attenuate the impact of disease modifying factors to protect neurological "outcome at risk". This putatively results in improved spinal cord injury medical care. TRIAL REGISTRATION DRKS-ID: DRKS00000122 (German Clinical Trials Registry).


Assuntos
Doenças Autoimunes do Sistema Nervoso/diagnóstico , Doenças Autoimunes do Sistema Nervoso/epidemiologia , Bases de Dados Factuais , Traumatismos da Medula Espinal/diagnóstico , Traumatismos da Medula Espinal/epidemiologia , Estudos de Viabilidade , Humanos , Internacionalidade , Estudos Longitudinais , Estudos Prospectivos
13.
Brain ; 135(Pt 11): 3238-50, 2012 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-23100450

RESUMO

Infections are a common threat to patients after spinal cord injury. Furthermore, infections might propagate neuronal death, and consequently contribute to the restriction of neurological recovery. We investigated the association of infections (i.e. pneumonia and/or postoperative wound infections) with functional neurological outcome after acute severe traumatic spinal cord injury. We screened data sets of 24 762 patients enrolled in a prospective cohort study (National Spinal Cord Injury Database, Birmingham, AL, USA). Patients were assessed according to the ASIA classification. ASIA impairment scale-classified A and B patients recruited within 24 h post-trauma (n = 1436) were selected as being a major recruitment population for interventional trials. Patients with documented pneumonia and/or postoperative wound infections (n = 581) were compared with control subjects (non-documented infections, n = 855). The functional neurological outcome parameters (i) upward ASIA impairment scale conversions; (ii) gain of ASIA motor scores; and (iii) gain of motor and sensory levels were consecutively analysed over time up to 1 year after spinal cord injury. The group with pneumonia and/or postoperative wound infections revealed less ASIA impairment scale upward conversions after 1 year than the control group (ASIA impairment scale A: 17.2 versus 23.9%, P = 0.03; ASIA impairment scale B: 57.1 versus 74.7%, P = 0.009). ASIA motor score gain [median (interquartile range)] was lower in patients with infections [ASIA impairment scale A: 8 (4-12) versus 10 (5-17), P = 0.01; ASIA impairment scale B: 19.5 (8-53.5) versus 42 (20.5-64), P = 0.03)]. Analysis of acquired motor/sensory levels supported these findings. In ASIA impairment scale A patients, the gain in motor levels (21.7 versus 33.3%, P = 0.04) and sensory levels (24.4 versus 38 of 102, 37.3%, P = 0.03) was significantly lower in the group with pneumonia and/or postoperative wound infections than in the control group. Multiple regression analysis identified pneumonia and/or postoperative wound infections as independent risk factors for impaired ASIA impairment scale upward conversion (odds ratio: 1.89, 95% confidence interval: 1.36-2.63, P < 0.0005) or lower gain in ASIA motor score (regression coefficient: -8.21, 95% confidence interval: -12.29 to -4.14, P < 0.0005). Infections associated with spinal cord injury, such as pneumonia and/or postoperative wound infections, qualify as independent risk factors for poor neurological outcome after motor complete spinal cord injury. Infections constitute a clinically relevant target for protecting the limited endogenous functional regeneration capacity. Upcoming interventional trials might gain in efficacy with improved patient stratification and might benefit from complementary protection of the intrinsic recovery potential after spinal cord injury.


Assuntos
Pneumonia/epidemiologia , Recuperação de Função Fisiológica , Traumatismos da Medula Espinal/epidemiologia , Infecção da Ferida Cirúrgica/epidemiologia , Adolescente , Adulto , Idoso , Estudos de Casos e Controles , Comorbidade , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Exame Neurológico/métodos , Exame Neurológico/estatística & dados numéricos , Estudos Prospectivos , Índice de Gravidade de Doença , Traumatismos da Medula Espinal/reabilitação , Infecção da Ferida Cirúrgica/complicações , Estados Unidos/epidemiologia
14.
Nat Commun ; 12(1): 781, 2021 02 03.
Artigo em Inglês | MEDLINE | ID: mdl-33536416

RESUMO

After complete spinal cord injuries (SCI), spinal segments below the lesion maintain inter-segmental communication via the intraspinal propriospinal network. However, it is unknown whether selective manipulation of these circuits can restore locomotor function in the absence of brain-derived inputs. By taking advantage of the compromised blood-spinal cord barrier following SCI, we optimized a set of procedures in which AAV9 vectors administered via the tail vein efficiently transduce neurons in lesion-adjacent spinal segments after a thoracic crush injury in adult mice. With this method, we used chemogenetic actuators to alter the excitability of propriospinal neurons in the thoracic cord of the adult mice with a complete thoracic crush injury. We showed that activating these thoracic neurons enables consistent and significant hindlimb stepping improvement, whereas direct manipulations of the neurons in the lumbar spinal cord led to muscle spasms without meaningful locomotion. Strikingly, manipulating either excitatory or inhibitory propriospinal neurons in the thoracic levels leads to distinct behavioural outcomes, with preferential effects on standing or stepping, two key elements of the locomotor function. These results demonstrate a strategy of engaging thoracic propriospinal neurons to improve hindlimb function and provide insights into optimizing neuromodulation-based strategies for treating SCI.


Assuntos
Dependovirus/genética , Membro Posterior/fisiopatologia , Locomoção/fisiologia , Neurônios/metabolismo , Traumatismos da Medula Espinal/fisiopatologia , Animais , Antipsicóticos/administração & dosagem , Clozapina/administração & dosagem , Clozapina/análogos & derivados , Vetores Genéticos/genética , Membro Posterior/inervação , Locomoção/efeitos dos fármacos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Medula Espinal/efeitos dos fármacos , Medula Espinal/metabolismo , Medula Espinal/fisiopatologia , Traumatismos da Medula Espinal/terapia
15.
Glia ; 58(14): 1748-56, 2010 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-20645410

RESUMO

Semaphorin 7A (Sema7A) is involved in the formation of the central nervous system during development by operating axon guidance and neuronal migration. We investigated the expression of the TGFß-inducible Sema7A following spinal cord injury (SCI). After SCI, Sema7A(+) cells accumulated specifically in lesion areas resulting in significantly enhanced Sema7A expression at the injury site (P < 0.0001). During the first days lesional Sema7A expression was confined to neurons, ballooned neurite fibers/retraction bulbs, and endothelial cells. At day 7, we observed Sema7A expression by components of the glial scar, such as reactive astrocytes and pronounced extracellular Sema7A deposition. In the direct perilesional rim, Sema7A(+) astrocytes coexpressed the activation-associated intermediate filament vimentin. In the injured spinal cord, numbers of Sema7A(+) cells reached maximum levels at day 14. The restricted accumulation of Sema7A(+) reactive astrocytes and Sema7A deposition in fibronectin(+) extracellular matrix territories suggests a participation of the fibrostimulatory Sema7A in the developing and maturating scar following SCI. In addition, Sema7A appears to be marker a for astrocyte activation.


Assuntos
Cicatriz/metabolismo , Cicatriz/patologia , Neuroglia/metabolismo , Neuroglia/patologia , Semaforinas/biossíntese , Traumatismos da Medula Espinal/metabolismo , Medula Espinal/metabolismo , Animais , Antígenos CD , Modelos Animais de Doenças , Fibrose , Gliose/metabolismo , Gliose/patologia , Masculino , Ratos , Ratos Endogâmicos Lew , Semaforinas/genética , Semaforinas/fisiologia , Medula Espinal/patologia , Traumatismos da Medula Espinal/patologia , Fator de Crescimento Transformador beta/fisiologia , Regulação para Cima/fisiologia
16.
Invest Ophthalmol Vis Sci ; 61(2): 31, 2020 02 07.
Artigo em Inglês | MEDLINE | ID: mdl-32084268

RESUMO

Purpose: To investigate the possible role of activating transcription factor 3 (ATF3) in retinal ganglion cell (RGC) neuroprotection and optic nerve regeneration after optic nerve crush (ONC). Methods: Overexpression of proteins of interest (ATF3, phosphatase and tensin homolog [PTEN], placental alkaline phosphatase, green fluorescent protein) in the retina was achieved by intravitreal injections of recombinant adenovirus-associated viruses (rAAVs) expressing corresponding proteins. The number of RGCs and αRGCs was evaluated by immunostaining retinal sections and whole-mount retinas with antibodies against RNA binding protein with multiple splicing (RBPMS) and osteopontin, respectively. Axonal regeneration was assessed via fluorophore-coupled cholera toxin subunit B labeling. RGC function was evaluated by recording positive scotopic threshold response. Results: The level of ATF3 is preferentially elevated in osteopontin+/RBPMS+ αRGCs following ONC. Overexpression of ATF3 by intravitreal injection of rAAV 2 weeks before ONC promoted RBPMS+ RGC survival and preserved RGC function as assessed by positive scotopic threshold response recordings 2 weeks after ONC. However, overexpression of ATF3 and simultaneous downregulation of PTEN, a negative regulator of the mTOR pathway, combined with ONC, only moderately promoted short distance RGC axon regeneration (200 µm from the lesion site) but did not provide additional RGC neuroprotection compared with PTEN downregulation alone. Conclusions: These results reveal a neuroprotective effect of ATF3 in the retina following injury and identify ATF3 as a promising agent for potential treatments of optic neuropathies.


Assuntos
Fator 3 Ativador da Transcrição/fisiologia , Neuroproteção/fisiologia , Traumatismos do Nervo Óptico/fisiopatologia , Células Ganglionares da Retina/fisiologia , Fator 3 Ativador da Transcrição/metabolismo , Animais , Axônios/patologia , Camundongos , Camundongos Endogâmicos C57BL , Compressão Nervosa , Regeneração Nervosa/fisiologia , Traumatismos do Nervo Óptico/metabolismo , Traumatismos do Nervo Óptico/patologia , Células Ganglionares da Retina/patologia
17.
Neuron ; 94(6): 1112-1120.e4, 2017 Jun 21.
Artigo em Inglês | MEDLINE | ID: mdl-28641110

RESUMO

At least 30 types of retinal ganglion cells (RGCs) send distinct messages through the optic nerve to the brain. Available strategies of promoting axon regeneration act on only some of these types. Here we tested the hypothesis that overexpressing developmentally important transcription factors in adult RGCs could reprogram them to a "youthful" growth-competent state and promote regeneration of other types. From a screen of transcription factors, we identified Sox11 as one that could induce substantial axon regeneration. Transcriptome profiling indicated that Sox11 activates genes involved in cytoskeletal remodeling and axon growth. Remarkably, α-RGCs, which preferentially regenerate following treatments such as Pten deletion, were killed by Sox11 overexpression. Thus, Sox11 promotes regeneration of non-α-RGCs, which are refractory to Pten deletion-induced regeneration. We conclude that Sox11 can reprogram adult RGCs to a growth-competent state, suggesting that different growth-promoting interventions promote regeneration in distinct neuronal types.


Assuntos
Axônios/metabolismo , Regeneração Nervosa/genética , Crescimento Neuronal/genética , Traumatismos do Nervo Óptico/metabolismo , Células Ganglionares da Retina/metabolismo , Fatores de Transcrição SOXC/genética , Animais , Sobrevivência Celular , Perfilação da Expressão Gênica , Camundongos , Microscopia de Fluorescência , Traumatismos do Nervo Óptico/patologia , PTEN Fosfo-Hidrolase/genética , Regeneração/genética , Retina/metabolismo , Retina/patologia , Células Ganglionares da Retina/citologia , Células Ganglionares da Retina/patologia , Fatores de Transcrição SOXC/metabolismo
18.
Nat Neurosci ; 20(11): 1549-1559, 2017 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-28920935

RESUMO

Acute spinal cord injury (SCI) causes systemic immunosuppression and life-threatening infections, thought to result from noradrenergic overactivation and excess glucocorticoid release via hypothalamus-pituitary-adrenal axis stimulation. Instead of consecutive hypothalamus-pituitary-adrenal axis activation, we report that acute SCI in mice induced suppression of serum norepinephrine and concomitant increase in cortisol, despite suppressed adrenocorticotropic hormone, indicating primary (adrenal) hypercortisolism. This neurogenic effect was more pronounced after high-thoracic level (Th1) SCI disconnecting adrenal gland innervation, compared with low-thoracic level (Th9) SCI. Prophylactic adrenalectomy completely prevented SCI-induced glucocorticoid excess and lymphocyte depletion but did not prevent pneumonia. When adrenalectomized mice were transplanted with denervated adrenal glands to restore physiologic glucocorticoid levels, the animals were completely protected from pneumonia. These findings identify a maladaptive sympathetic-neuroendocrine adrenal reflex mediating immunosuppression after SCI, implying that therapeutic normalization of the glucocorticoid and catecholamine imbalance in SCI patients could be a strategy to prevent detrimental infections.


Assuntos
Glândulas Suprarrenais/imunologia , Sistema Hipotálamo-Hipofisário/imunologia , Tolerância Imunológica/imunologia , Sistema Hipófise-Suprarrenal/imunologia , Reflexo/imunologia , Traumatismos da Medula Espinal/imunologia , Glândulas Suprarrenais/transplante , Adrenalectomia/efeitos adversos , Adrenalectomia/métodos , Adulto , Idoso , Animais , Feminino , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Pessoa de Meia-Idade , Método Simples-Cego , Traumatismos da Medula Espinal/complicações , Traumatismos da Medula Espinal/cirurgia , Vértebras Torácicas/lesões
19.
Exp Neurol ; 279: 261-273, 2016 May.
Artigo em Inglês | MEDLINE | ID: mdl-26875994

RESUMO

Most in vivo spinal cord injury (SCI) experimental models use rodents. Due to the anatomical and functional differences between rodents and humans, reliable large animal models, such as non-human primates, of SCI are critically needed to facilitate translation of laboratory discoveries to clinical applications. Here we report the establishment of a controlled spinal contusion model that produces severity-dependent functional and histological deficits in non-human primates. Six adult male rhesus macaque monkeys underwent mild to moderate contusive SCI using 1.0 and 1.5mm tissue displacement injuries at T9 or sham laminectomy (n=2/group). Multiple assessments including motor-evoked potential (MEP), somatosensory-evoked potential (SSEP), MR imaging, and monkey hindlimb score (MHS) were performed. Monkeys were sacrificed at 6 months post-injury, and the lesion area was examined for cavitation, axons, myelin, and astrocytic responses. The MHS demonstrated that both the 1.0 and 1.5mm displacement injuries created discriminative neurological deficits which were severity-dependent. The MEP response rate was depressed after a 1.0mm injury and was abolished after a 1.5mm injury. The SSEP response rate was slightly decreased following both the 1.0 and 1.5mm SCI. MRI imaging demonstrated an increase in T2 signal at the lesion site at 3 and 6months, and diffusion tensor imaging (DTI) tractography showed interrupted fiber tracts at the lesion site at 4h and at 6 months post-SCI. Histologically, severity-dependent spinal cord atrophy, axonal degeneration, and myelin loss were found after both injury severities. Notably, strong astrocytic gliosis was not observed at the lesion penumbra in the monkey. In summary, we describe the development of a clinically-relevant contusive SCI model that produces severity-dependent anatomical and functional deficits in non-human primates. Such a model may advance the translation of novel SCI repair strategies to the clinic.


Assuntos
Contusões/patologia , Traumatismos da Medula Espinal/patologia , Animais , Astrócitos/patologia , Atrofia , Axônios/patologia , Comportamento Animal , Contusões/psicologia , Modelos Animais de Doenças , Potencial Evocado Motor , Potenciais Somatossensoriais Evocados , Gliose/patologia , Membro Posterior , Locomoção , Macaca mulatta , Masculino , Bainha de Mielina/patologia , Medula Espinal/patologia , Traumatismos da Medula Espinal/psicologia
20.
Funct Neurol ; 30(4): 229-36, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26727701

RESUMO

Nociception is an important protective mechanism. The Hargreaves method, which involves measuring withdrawal latency following thermal stimulation to Thermal nociception using a modified Hargreaves method in primates and humans the paw, is commonly used to measure pain thresholds in rodents. We modified this technique to measure pain thresholds in monkeys and humans. The modified Hargreaves method was used to quantitate pain sensitivity in eight normal rhesus monkeys, 55 human volunteers, and 12 patients with spinal cord or cauda equina lesions. Thermal stimulation was delivered at 80% of maximum output, and the duration of the stimulation was set at a maximum of 10 seconds to avoid skin injury. The following withdrawal latencies were recorded: 2.7 ± 0.12 seconds in volunteers and 3.4 ± 0.35 seconds in neurologically intact monkeys (p>0.05). Patients with spinal cord or cauda equina lesions showed significantly increased latencies (p<0.001). The modified Hargreaves technique is a safe and reliable method that can provide a validated measure of physiological pain sensation.


Assuntos
Comportamento Animal/fisiologia , Nociceptividade/fisiologia , Limiar da Dor/fisiologia , Pele/fisiopatologia , Animais , Feminino , Macaca mulatta , Masculino , Modelos Animais , Medição da Dor/métodos , Fenômenos Fisiológicos da Pele
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