RESUMO
INTRODUCTION: A recent study from our laboratory demonstrated a number of neurobehavioral abnormalities in mice colony injected with a mouse-weight equivalent dose of all vaccines that are administered to infants in their first 18 months of life according to the U. S. pediatric vaccination schedule.Cytokines have been studied extensively as blood immune and inflammatory biomarkers, and their association with neurodevelopmental disorders. Given the importance of cytokines in early neurodevelopment, we aimed to investigate the potential post-administration effects of the U. S. pediatric vaccines on circulatory cytokines in a mouse model.In the current study, cytokines have been assayed at early and late time points in mice vaccinated early in postnatal life and compared with placebo controls. MATERIALS AND METHODS: Newborn mouse pups were divided into three groups: i) vaccine (V1), ii) vaccine â× â3 (V3) and iii) placebo control. V1 group was injected with mouse weight-equivalent of the current U. S. pediatric vaccine schedule. V3 group was injected with same vaccines but at triple the dose and the placebo control was injected with saline. Pups were also divided according to the sampling age into two main groups: acute- and chronic-phase group. Blood samples were collected at postnatal day (PND) 23, two days following vaccine schedule for the acute-phase group or at 67 weeks post-vaccination for the chronic-phase groups. Fifteen cytokines were analyzed: GM-CSF, IFN-γ, IL-1ß, IL-2, IL-4, IL-5, IL-6, IL-9, IL-10, IL-12p70, IL-13, IL-17A, MCP-1, TNF-α, and VEGF-A. Wilcoxon Rank Sum test or unpaired Student's t-test was performed where applicable. RESULTS: IL-5 levels in plasma were significantly elevated in the V1 and V3 group compared with the control only in the acute-phase group. The elevation of IL-5 levels in the two vaccine groups were significant irrespective of whether the sexes were combined or analyzed separately. Other cytokines (VEGF-A, TNF-α, IL-10, MCP-1, GM-CSF, IL-6, and IL-13) were also impacted, although to a lesser extent and in a sex-dependent manner. In the acute-phase group, females showed a significant increase in IL-10 and MCP-1 levels and a decrease in VEGF-A levels in both V1 and V3 group compared to controls. In the acute-phase, a significant increase in MCP-1 levels in V3 group and CM-CSF levels in V1 and V3 group and decrease in TNF-α levels in V1 group were observed in treated males as compared with controls. In chronic-phase females, levels of VEGF-A in V1 and V3 group, TNF-α in V3 group, and IL-13 in V1 group were significantly decreased in contrast with controls. In chronic-phase males, TNF-α levels were significantly increased in V1 group and IL-6 levels decreased in V3 group in comparison to controls. The changes in levels of most tested cytokines were altered between the early and the late postnatal assays. CONCLUSIONS: IL-5 levels significantly increased in the acute-phase of the treatment in the plasma of both sexes that were subjected to V1 and V3 injections. These increases had diminished by the second test assayed at week 67. These results suggest that a profound, albeit transient, effect on cytokine levels may be induced by the whole vaccine administration supporting our recently published observations regarding the behavioral abnormalities in the same mice. These observations support the view that the administration of whole pediatric vaccines in a neonatal period may impact at least short-term CNS functions in mice.
Assuntos
Artrite Psoriásica/tratamento farmacológico , Doenças Inflamatórias Intestinais/complicações , Psoríase/complicações , Anticorpos Monoclonais Humanizados/uso terapêutico , Artrite Psoriásica/complicações , Fármacos Dermatológicos/uso terapêutico , Humanos , Masculino , Pessoa de Meia-Idade , Psoríase/tratamento farmacológico , Ustekinumab/uso terapêuticoRESUMO
Essentials The rs773902 SNP results in differences in platelet protease-activated receptor (PAR4) function. The functional consequences of rs773902 were analyzed in human platelets and stroke patients. rs773902 affects thrombin-induced platelet function, PAR4 desensitization, stroke association. Enhanced PAR4 Thr120 effects on platelet function are blocked by ticagrelor. SUMMARY: Background F2RL3 encodes protease-activated receptor (PAR) 4 and harbors an A/G single-nucleotide polymorphism (SNP) (rs773902) with racially dimorphic allelic frequencies. This SNP mediates an alanine to threonine substitution at residue 120 that alters platelet PAR4 activation by the artificial PAR4-activation peptide (PAR4-AP) AYPGKF. Objectives To determine the functional effects of rs773902 on stimulation by a physiological agonist, thrombin, and on antiplatelet antagonist activity. Methods Healthy human donors were screened and genotyped for rs773902. Platelet function in response to thrombin was assessed without and with antiplatelet antagonists. The association of rs773902 alleles with stroke was assessed in the Stroke Genetics Network study. Results As compared with rs773902 GG donors, platelets from rs773902 AA donors had increased aggregation in response to subnanomolar concentrations of thrombin, increased granule secretion, and decreased sensitivity to PAR4 desensitization. In the presence of PAR1 blockade, this genotype effect was abolished by higher concentrations of or longer exposure to thrombin. We were unable to detect a genotype effect on thrombin-induced PAR4 cleavage, dimerization, and lipid raft localization; however, rs773902 AA platelets required a three-fold higher level of PAR4-AP for receptor desensitization. Ticagrelor, but not vorapaxar, abolished the PAR4 variant effect on thrombin-induced platelet aggregation. A significant association of modest effect was detected between the rs773902 A allele and stroke. Conclusion The F2RL3 rs773902 SNP alters platelet reactivity to thrombin; the allelic effect requires P2Y12 , and is not affected by gender. Ticagrelor blocks the enhanced reactivity of rs773902 A platelets. PAR4 encoded by the rs773902 A allele is relatively resistant to desensitization and may contribute to stroke risk.
Assuntos
Plaquetas/efeitos dos fármacos , Variantes Farmacogenômicos , Inibidores da Agregação Plaquetária/farmacologia , Polimorfismo de Nucleotídeo Único , Antagonistas do Receptor Purinérgico P2Y/farmacologia , Receptores Purinérgicos P2Y12/efeitos dos fármacos , Receptores de Trombina/agonistas , Receptores de Trombina/genética , Trombina/farmacologia , Ticagrelor/farmacologia , Adulto , Animais , Plaquetas/metabolismo , Células COS , Chlorocebus aethiops , Interações Medicamentosas , Feminino , Células HEK293 , Humanos , Masculino , Pessoa de Meia-Idade , Agregação Plaquetária/efeitos dos fármacos , Receptores Purinérgicos P2Y12/metabolismo , Receptores de Trombina/metabolismo , Fatores de Risco , Acidente Vascular Cerebral/sangue , Acidente Vascular Cerebral/genética , Adulto JovemRESUMO
In areas without newborn screening for severe combined immunodeficiency (SCID), disease-defining infections may lead to diagnosis, and in some cases, may not be identified prior to the first year of life. We describe a female infant who presented with disseminated vaccine-acquired varicella (VZV) and vaccine-acquired rubella infections at 13 months of age. Immunological evaluations demonstrated neutropenia, isolated CD4 lymphocytopenia, the presence of CD8(+) T cells, poor lymphocyte proliferation, hypergammaglobulinaemia and poor specific antibody production to VZV infection and routine immunizations. A combination of whole exome sequencing and custom-designed chromosomal microarray with exon coverage of primary immunodeficiency genes detected compound heterozygous mutations (one single nucleotide variant and one intragenic copy number variant involving one exon) within the IL7R gene. Mosaicism for wild-type allele (20-30%) was detected in pretransplant blood and buccal DNA and maternal engraftment (5-10%) demonstrated in pretransplant blood DNA. This may be responsible for the patient's unusual immunological phenotype compared to classical interleukin (IL)-7Rα deficiency. Disseminated VZV was controlled with anti-viral and immune-based therapy, and umbilical cord blood stem cell transplantation was successful. Retrospectively performed T cell receptor excision circle (TREC) analyses completed on neonatal Guthrie cards identified absent TREC. This case emphasizes the danger of live viral vaccination in severe combined immunodeficiency (SCID) patients and the importance of newborn screening to identify patients prior to high-risk exposures. It also illustrates the value of aggressive pathogen identification and treatment, the influence newborn screening can have on morbidity and mortality and the significant impact of newer genomic diagnostic tools in identifying the underlying genetic aetiology for SCID patients.
Assuntos
Linfócitos T CD4-Positivos/imunologia , Varicela/etiologia , Linfopenia/etiologia , Mutação , Receptores de Interleucina-7/genética , Rubéola (Sarampo Alemão)/etiologia , Imunodeficiência Combinada Severa/genética , Vacinação/efeitos adversos , Variações do Número de Cópias de DNA , Exoma , Feminino , Humanos , Lactente , Análise de Sequência com Séries de Oligonucleotídeos , Imunodeficiência Combinada Severa/imunologiaRESUMO
Our previous ecological studies of autism spectrum disorder (ASD) has demonstrated a correlation between increasing ASD rates and aluminium (Al) adjuvants in common use in paediatric vaccines in several Western countries. The correlation between ASD rate and Al adjuvant amounts appears to be dose-dependent and satisfies 8 of 9 Hill criteria for causality. We have now sought to provide an animal model to explore potential behavioural phenotypes and central nervous system (CNS) alterations using s.c. injections of Al hydroxide in early postnatal CD-1 mice of both sexes. Injections of a "high" and "low" Al adjuvant levels were designed to correlate to either the U.S. or Scandinavian paediatric vaccine schedules vs. control saline-injected mice. Both male and female mice in the "high Al" group showed significant weight gains following treatment up to sacrifice at 6 months of age. Male mice in the "high Al" group showed significant changes in light-dark box tests and in various measures of behaviour in an open field. Female mice showed significant changes in the light-dark box at both doses, but no significant changes in open field behaviours. These current data implicate Al injected in early postnatal life in some CNS alterations that may be relevant for a better understanding of the aetiology of ASD.
Assuntos
Alumínio/toxicidade , Comportamento Animal/efeitos dos fármacos , Atividade Motora/efeitos dos fármacos , Doenças do Sistema Nervoso/fisiopatologia , Adjuvantes Imunológicos/administração & dosagem , Adjuvantes Imunológicos/toxicidade , Alumínio/administração & dosagem , Hidróxido de Alumínio/administração & dosagem , Hidróxido de Alumínio/toxicidade , Animais , Animais Recém-Nascidos , Relação Dose-Resposta a Droga , Feminino , Humanos , Injeções Subcutâneas , Masculino , Camundongos , Doenças do Sistema Nervoso/induzido quimicamente , Fatores Sexuais , Fatores de Tempo , Aumento de Peso/efeitos dos fármacosRESUMO
We have examined the neurotoxicity of aluminum in humans and animals under various conditions, following different routes of administration, and provide an overview of the various associated disease states. The literature demonstrates clearly negative impacts of aluminum on the nervous system across the age span. In adults, aluminum exposure can lead to apparently age-related neurological deficits resembling Alzheimer's and has been linked to this disease and to the Guamanian variant, ALS-PDC. Similar outcomes have been found in animal models. In addition, injection of aluminum adjuvants in an attempt to model Gulf War syndrome and associated neurological deficits leads to an ALS phenotype in young male mice. In young children, a highly significant correlation exists between the number of pediatric aluminum-adjuvanted vaccines administered and the rate of autism spectrum disorders. Many of the features of aluminum-induced neurotoxicity may arise, in part, from autoimmune reactions, as part of the ASIA syndrome.
Assuntos
Adjuvantes Farmacêuticos/efeitos adversos , Alumínio/efeitos adversos , Doença de Alzheimer/induzido quimicamente , Esclerose Lateral Amiotrófica/induzido quimicamente , Sistema Nervoso Central/efeitos dos fármacos , Transtornos Globais do Desenvolvimento Infantil/induzido quimicamente , Síndrome do Golfo Pérsico/induzido quimicamente , Vacinas/efeitos adversos , Adulto , Animais , Autoimunidade/efeitos dos fármacos , Sistema Nervoso Central/imunologia , Criança , Modelos Animais de Doenças , Humanos , Masculino , CamundongosRESUMO
Genetic variation, both single-nucleotide variations and copy number variations (CNV), contribute to changes in gene expression. In some cases these variations are meaningfully correlated with disease states. We hypothesized that in a genetically heterogeneous disorder such as sporadic Alzheimer's disease (AD), utilizing gene expression as a quantitative trait and CNVs as a genetic marker map within the same individuals in the context of case-control status may increase the power to detect relevant loci. Using this approach an 8-kb deletion was identified that contains a PAX6-binding site on chr2q33.3 upstream of CREB1 encoding the cAMP responsive element-binding protein1 transcription factor. The association of the CNV to AD was confirmed by a case-control association study consisting of the Texas Alzheimer Research and Care Consortium and NIA-LOAD Family Study data sets.
Assuntos
Doença de Alzheimer/genética , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/metabolismo , Estudos de Casos e Controles , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Variações do Número de Cópias de DNA , Proteínas do Olho/metabolismo , Feminino , Perfilação da Expressão Gênica , Predisposição Genética para Doença , Genótipo , Proteínas de Homeodomínio/metabolismo , Humanos , Masculino , Pessoa de Meia-Idade , Fator de Transcrição PAX6 , Fatores de Transcrição Box Pareados/metabolismo , Proteínas Repressoras/metabolismoRESUMO
Immune challenges during early development, including those vaccine-induced, can lead to permanent detrimental alterations of the brain and immune function. Experimental evidence also shows that simultaneous administration of as little as two to three immune adjuvants can overcome genetic resistance to autoimmunity. In some developed countries, by the time children are 4 to 6 years old, they will have received a total of 126 antigenic compounds along with high amounts of aluminum (Al) adjuvants through routine vaccinations. According to the US Food and Drug Administration, safety assessments for vaccines have often not included appropriate toxicity studies because vaccines have not been viewed as inherently toxic. Taken together, these observations raise plausible concerns about the overall safety of current childhood vaccination programs. When assessing adjuvant toxicity in children, several key points ought to be considered: (i) infants and children should not be viewed as "small adults" with regard to toxicological risk as their unique physiology makes them much more vulnerable to toxic insults; (ii) in adult humans Al vaccine adjuvants have been linked to a variety of serious autoimmune and inflammatory conditions (i.e., "ASIA"), yet children are regularly exposed to much higher amounts of Al from vaccines than adults; (iii) it is often assumed that peripheral immune responses do not affect brain function. However, it is now clearly established that there is a bidirectional neuro-immune cross-talk that plays crucial roles in immunoregulation as well as brain function. In turn, perturbations of the neuro-immune axis have been demonstrated in many autoimmune diseases encompassed in "ASIA" and are thought to be driven by a hyperactive immune response; and (iv) the same components of the neuro-immune axis that play key roles in brain development and immune function are heavily targeted by Al adjuvants. In summary, research evidence shows that increasing concerns about current vaccination practices may indeed be warranted. Because children may be most at risk of vaccine-induced complications, a rigorous evaluation of the vaccine-related adverse health impacts in the pediatric population is urgently needed.
Assuntos
Adjuvantes Imunológicos/toxicidade , Alumínio/imunologia , Alumínio/toxicidade , Autoimunidade/imunologia , Adulto , Doenças Autoimunes/induzido quimicamente , Doenças Autoimunes/imunologia , Criança , Pré-Escolar , Humanos , Vacinação , Vacinas/efeitos adversosRESUMO
Aluminum is an experimentally demonstrated neurotoxin and the most commonly used vaccine adjuvant. Despite almost 90 years of widespread use of aluminum adjuvants, medical science's understanding about their mechanisms of action is still remarkably poor. There is also a concerning scarcity of data on toxicology and pharmacokinetics of these compounds. In spite of this, the notion that aluminum in vaccines is safe appears to be widely accepted. Experimental research, however, clearly shows that aluminum adjuvants have a potential to induce serious immunological disorders in humans. In particular, aluminum in adjuvant form carries a risk for autoimmunity, long-term brain inflammation and associated neurological complications and may thus have profound and widespread adverse health consequences. In our opinion, the possibility that vaccine benefits may have been overrated and the risk of potential adverse effects underestimated, has not been rigorously evaluated in the medical and scientific community. We hope that the present paper will provide a framework for a much needed and long overdue assessment of this highly contentious medical issue.
Assuntos
Adjuvantes Imunológicos/efeitos adversos , Alumínio/efeitos adversos , Vacinas/efeitos adversos , Animais , Vacinas contra Antraz/efeitos adversos , Doenças Autoimunes do Sistema Nervoso/induzido quimicamente , Carga Corporal (Radioterapia) , Criança , Pré-Escolar , Humanos , Lactente , Placebos/efeitos adversosRESUMO
OBJECTIVES: Copy number variants (CNVs) have been recognized as a source of genetic variation that contributes to disease phenotypes. Alzheimer disease (AD) has high heritability for occurrence and age at onset (AAO). We performed a cases-only genome-wide CNV association study for age at onset of AD. METHODS: The discovery case series (n = 40 subjects with AD) was evaluated using array comparative genome hybridization (aCGH). A replication case series (n = 507 subjects with AD) was evaluated using Affymetrix array (n = 243) and multiplex ligation-dependent probe amplification (n = 264). Hazard models related onset age to CNV. RESULTS: The discovery sample identified a chromosomal segment on 14q11.2 (19.3-19.5 Mb, NCBI build 36, UCSC hg18 March 2006) as a region of interest (genome-wide adjusted p = 0.032) for association with AAO of AD. This region encompasses a cluster of olfactory receptors. The replication sample confirmed the association (p = 0.035). The association was found for each APOE4 gene dosage (0, 1, and 2). CONCLUSION: High copy number in the olfactory receptor region on 14q11.2 is associated with younger age at onset of AD.
Assuntos
Doença de Alzheimer/epidemiologia , Doença de Alzheimer/genética , Variações do Número de Cópias de DNA , Idade de Início , Apolipoproteína E4/genética , Mapeamento Cromossômico , Cromossomos Humanos Par 14/genética , Estudos de Coortes , Hibridização Genômica Comparativa , Dosagem de Genes , Humanos , Modelos de Riscos Proporcionais , Receptores Odorantes/genéticaAssuntos
Diamino Aminoácidos/metabolismo , Córtex Cerebral/metabolismo , Neurotoxinas/metabolismo , Idoso , Idoso de 80 Anos ou mais , Diamino Aminoácidos/análise , Autopsia , Cromatografia Líquida de Alta Pressão , Toxinas de Cianobactérias , Doenças Endêmicas , Feminino , Guam/epidemiologia , Humanos , Espectroscopia de Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Neurotoxinas/análise , Doença de Parkinson/epidemiologia , Doença de Parkinson/metabolismo , Técnica de Diluição de Radioisótopos , Washington/epidemiologiaRESUMO
Mutations in ROR2, encoding a receptor tyrosine kinase, can cause autosomal recessive Robinow syndrome (RRS), a severe skeletal dysplasia with limb shortening, brachydactyly, and a dysmorphic facial appearance. Other mutations in ROR2 result in the autosomal dominant disease, brachydactyly type B (BDB1). No functional mechanisms have been delineated to effectively explain the association between mutations and different modes of inheritance causing different phenotypes. BDB1-causing mutations in ROR2 result from heterozygous premature termination codons (PTCs) in downstream exons and the conveyed phenotype segregates as an autosomal dominant trait, whereas heterozygous missense mutations and PTCs in upstream exons result in carrier status for RRS. Given that the distribution of PTC mutations revealed a correlation between the phenotype and the mode of inheritance conveyed, we investigated the potential role for the nonsense-mediated decay (NMD) pathway in the abrogation of possible aberrant effects of selected mutant alleles. Our experiments show that triggering or escaping NMD may cause different phenotypes with a distinct mode of inheritance. We generalize these findings to other disease-associated genes by examining PTC mutation distribution correlation with conveyed phenotype and inheritance patterns. Indeed, NMD may explain distinct phenotypes and different inheritance patterns conveyed by allelic truncating mutations enabling better genotype-phenotype correlations in several other disorders.
Assuntos
Anormalidades Múltiplas/genética , Alelos , Genes Dominantes , Genes Recessivos , Padrões de Herança , Mutação , Doenças do Desenvolvimento Ósseo/genética , Células Cultivadas , Humanos , Deformidades Congênitas dos Membros/genética , Fenótipo , Receptores Órfãos Semelhantes a Receptor Tirosina Quinase , Receptores de Superfície Celular/genética , SíndromeRESUMO
Epidemiological studies of the Guamanian variants of amyotrophic lateral sclerosis (ALS) and parkinsonism, amyotrophic lateral sclerosis-parkinsonism dementia complex (ALS-PDC), have shown a positive correlation between consumption of washed cycad seed flour and disease occurrence. Previous in vivo studies by our group have shown that the same seed flour induces ALS and PDC phenotypes in out bred adult male mice. In vitro studies using isolated cycad compounds have also demonstrated that several of these are neurotoxic, specifically, a number of water insoluble phytosterol glucosides of which beta-sitosterol beta-D: -glucoside (BSSG) forms the largest fraction. BSSG is neurotoxic to motor neurons and other neuronal populations in culture. The present study shows that an in vitro hybrid motor neuron (NSC-34) culture treated with BSSG undergoes a dose-dependent cell loss. Surviving cells show increased expression of HSP70, decreased cytosolic heavy neurofilament expression, and have various morphological abnormalities. CD-1 mice fed mouse chow pellets containing BSSG for 15 weeks showed motor deficits and motor neuron loss in the lumbar and thoracic spinal cord, along with decreased glutamate transporter labelling, and increased glial fibrillary acid protein reactivity. Other pathological outcomes included increased caspase-3 labelling in the striatum and decreased tyrosine-hydroxylase labelling in the striatum and substantia nigra. C57BL/6 mice fed BSSG-treated pellets for 10 weeks exhibited progressive loss of motor neurons in the lumbar spinal cord that continued to worsen even after the BSSG exposure ended. These results provide further support implicating sterol glucosides as one potential causal factor in the motor neuron pathology previously associated with cycad consumption and ALS-PDC.
Assuntos
Esclerose Lateral Amiotrófica/patologia , Demência/patologia , Neurônios Motores/patologia , Transtornos Parkinsonianos/patologia , Sitosteroides/farmacologia , Esclerose Lateral Amiotrófica/induzido quimicamente , Esclerose Lateral Amiotrófica/metabolismo , Animais , Caspase 3/metabolismo , Células Cultivadas , Corpo Estriado/metabolismo , Corpo Estriado/patologia , Demência/induzido quimicamente , Demência/metabolismo , Dieta , Proteínas de Choque Térmico HSP70/metabolismo , Masculino , Camundongos , Neurônios Motores/efeitos dos fármacos , Transtornos Parkinsonianos/induzido quimicamente , Transtornos Parkinsonianos/metabolismo , Medula Espinal/metabolismo , Medula Espinal/patologia , Substância Negra/metabolismo , Substância Negra/patologia , Tirosina 3-Mono-Oxigenase/metabolismoRESUMO
Glutathione (reduced form GSH and oxidized form GSSG) constitutes an important defense against oxidative stress in the brain, and taurine is an inhibitory neuromodulator particularly in the developing brain. The effects of GSH and GSSG and glycylglycine, gamma-glutamylcysteine, cysteinylglycine, glycine and cysteine on the release of [(3)H]taurine evoked by K+-depolarization or the ionotropic glutamate receptor agonists glutamate, kainate, 2-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA) and N-methyl-D-aspartate (NMDA) were now studied in slices from the hippocampi from 7-day-old mouse pups in a perfusion system. All stimulatory agents (50 mM K(+), 1 mM glutamate, 0.1 mM kainate, 0.1 mM AMPA and 0.1 mM NMDA) evoked taurine release in a receptor-mediated manner. Both GSH and GSSG significantly inhibited the release evoked by 50 mM K+. The release induced by AMPA and glutamate was also inhibited, while the kainate-evoked release was significantly activated by both GSH and GSSG. The NMDA-evoked release proved the most sensitive to modulation: L-Cysteine and glycine enhanced the release in a concentration-dependent manner, whereas GSH and GSSG were inhibitory at low (0.1 mM) but not at higher (1 or 10 mM) concentrations. The release evoked by 0.1 mM AMPA was inhibited by gamma-glutamylcysteine and cysteinylglycine, whereas glycylglycine had no effect. The 0.1 mM NMDA-evoked release was inhibited by glycylglycine and gamma-glutamylcysteine. In turn, cysteinylglycine inhibited the NMDA-evoked release at 0.1 mM, but was inactive at 1 mM. Glutathione exhibited both enhancing and attenuating effects on taurine release, depending on the glutathione concentration and on the agonist used. Both glutathione and taurine act as endogenous neuroprotective effectors during early postnatal life.
Assuntos
Glutationa/análogos & derivados , Glutationa/farmacologia , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Taurina/metabolismo , Animais , Feminino , Hipocampo/crescimento & desenvolvimento , Masculino , Camundongos , Potássio/farmacologiaRESUMO
Although sildenafil (Viagra) and other phosphodiesterase V (PDE V) inhibitors are increasingly recognized for their use in the treatment of male erectile dysfunction and perhaps more recently pulmonary artery hypertension, less is known of their potential beneficial effects in other situations. Medeiros et al., in the current issue of the British Journal of Pharmacology, report that sildenafil dramatically reduces alcohol-induced gastric damage in rats. The authors provide convincing evidence that such protection not only occurs via the nitric oxide (NO)/cGMP pathway, but also involves regulation of ATP-sensitive potassium channels. Therefore, in addition to exerting anti-impotence efficacy, PDE V inhibitors may provide significant beneficial effects from mucosal injury induced by alcohol.
Assuntos
GMP Cíclico/metabolismo , Mucosa Gástrica/efeitos dos fármacos , Canais KATP/metabolismo , Óxido Nítrico/metabolismo , Úlcera Péptica Hemorrágica/prevenção & controle , Inibidores de Fosfodiesterase/farmacologia , Piperazinas/farmacologia , Úlcera Gástrica/prevenção & controle , Sulfonas/farmacologia , Animais , Arginina/metabolismo , Nucleotídeo Cíclico Fosfodiesterase do Tipo 5/metabolismo , Modelos Animais de Doenças , Etanol , Mucosa Gástrica/enzimologia , Mucosa Gástrica/metabolismo , Mucosa Gástrica/patologia , Glutationa/metabolismo , Guanilato Ciclase/metabolismo , Hemoglobinas/metabolismo , Canais KATP/efeitos dos fármacos , Óxido Nítrico Sintase/metabolismo , Úlcera Péptica Hemorrágica/etiologia , Úlcera Péptica Hemorrágica/metabolismo , Úlcera Péptica Hemorrágica/patologia , Inibidores da Fosfodiesterase 5 , Inibidores de Fosfodiesterase/uso terapêutico , Piperazinas/uso terapêutico , Purinas/farmacologia , Purinas/uso terapêutico , Ratos , Transdução de Sinais/efeitos dos fármacos , Citrato de Sildenafila , Úlcera Gástrica/induzido quimicamente , Úlcera Gástrica/complicações , Úlcera Gástrica/metabolismo , Úlcera Gástrica/patologia , Sulfonas/uso terapêuticoRESUMO
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that primarily affects motor neurons and descending motor tracts of the CNS. We have evaluated the CNS of a murine model of familial ALS based on the over-expression of mutant human superoxide dismutase (mSOD; G93A) using magnetic resonance microscopy (MRM) and immunohistochemistry (IHC). Three-dimensional volumetric analysis was performed from 3D T2*-weighted images acquired at 17.6 T at isotropic resolutions of 40 mum. Compared to controls, mSOD mice had significant reductions in the volumes of total brain, substantia nigra, striatum, hippocampus, and internal capsule, with decreased cortical thickness in primary motor and somatosensory cortices. In the spinal cord, mSOD mice had significantly decreased volume of both the total grey and white matter; in the latter case, the volume change was confined to the dorsal white matter. Increased apoptosis, GFAP positive astrocytes, and/or activated microglia were observed in all those CNS regions that showed volume loss except for the hippocampus. The MRM findings in mSOD over-expressing mice are similar to data previously obtained from a model of ALS-parkinsonism dementia complex (ALS-PDC), in which neural damage occurred following a diet of washed cycad flour containing various neurotoxins. The primary difference between the two models involves a significantly greater decrease in spinal cord white matter volume in mSOD mice, perhaps reflecting variations in degeneration of the descending motor tracts. The extent to which several CNS structures are impacted in both murine models of ALS argues for a reevaluation of the nature of the pathogenesis of ALS since CNS structures involved in Parkinson's and Alzheimer's diseases appear to be affected as well.
Assuntos
Esclerose Lateral Amiotrófica/patologia , Encéfalo/patologia , Mutação , Medula Espinal/patologia , Superóxido Dismutase/metabolismo , Esclerose Lateral Amiotrófica/genética , Animais , Encéfalo/metabolismo , Proteínas de Ligação ao Cálcio/metabolismo , Caspase 3/metabolismo , Ativação Enzimática , Proteína Glial Fibrilar Ácida/metabolismo , Imuno-Histoquímica , Camundongos , Camundongos Transgênicos , Proteínas dos Microfilamentos , Microscopia , Medula Espinal/metabolismo , Superóxido Dismutase/genéticaRESUMO
Excitotoxicity has been widely hypothesized to play a major role in various neurodegenerative diseases. We have used a mouse model of ALS-parkinsonism dementia complex (ALS-PDC) of the Western Pacific to explore this hypothesis. Mice fed washed cycad flour, the major epidemiological link to ALS-PDC, showed significant and progressive motor, cognitive, and sensory behavioural deficits [Wilson, J.M., Khabazian, I., Wong, M.C., Seyedalikhani, A., Bains, J.S., Pasqualotto, B.A., Williams, D.E., Andersen, R.J., Simpson, R.J., Smith, R., Craig, U.K., Kurland, L.T., Shaw, C.A., 2002. Behavioral and neurological correlates of ALS-parkinsonism dementia complex in adult mice fed washed cycad flour. Neuromol. Med. 1 (3), 207-221]. In addition, glutamate transporter (GLT-1/EAAT2) levels measured by immunohistochemistry with antibodies specific for two glial glutamate transporter splice variants (GLT-1alpha and GLT-1B) were significantly down-regulated showing a 'patchy' loss of antibody label centered on blood vessels [Wilson, J.M., Khabazian, I., Pow, D.V., Craig, U.K., Shaw, C.A., 2003. Decrease in glial glutamate transporter variants and excitatory amino acid receptor down-regulation in a murine model of ALS-PDC. Neuromol. Med. 3 (2), 105-118]. Receptor binding assays showed decreased NMDA and AMPA receptor levels combined with increased GABA(A) receptor levels in various CNS regions. The alterations in GLT-1 variants and the ionotropic receptors are consistent with an increased level of extracellular glutamate. The interaction between environmental toxicity and genetic susceptibility was also tested using mice expressing various Apolipoprotein E (ApoE) genotypes. Mice lacking the ApoE gene showed relative resistance to cycad-induced toxicity as measured by GLT-1B labeling, but all mice expressing the human ApoE isoforms showed a similar loss of GLT-1B. We have further shown that an isolated cycad toxin (beta-sitosterol-beta-d-glucoside, BSSG), previously shown to release glutamate in vitro [Wilson, J.M., Khabazian, I., Wong, M.C., Seyedalikhani, A., Bains, J.S., Pasqualotto, B.A., Williams, D.E., Andersen, R.J., Simpson, R.J., Smith, R., Craig, U.K., Kurland, L.T., Shaw, C.A., 2002. Behavioral and neurological correlates of ALS-parkinsonism dementia complex in adult mice fed washed cycad flour. Neuromol. Med. 1 (3), 207-221], can be directly toxic to motor neurons in vivo [Wilson, J.M., Petrik, M.S., Moghadasian, M.H., Shaw, C.A., 2005. Examining the interaction of apo E and neurotoxicity on a murine model of ALS-PDC. Can. J. Physiol. Pharmacol. 83 (2), 131-141]. However, BSSG-fed mice did not show altered GLT-1B labeling in the spinal cord suggesting that an initial excitotoxic mechanism may not be responsible for the final neuronal loss observed. While glutamate-mediated excitotoxicity is likely involved in the outcomes following cycad/BSSG exposure, the precise location in the cascade of events ultimately leading to neuronal death remains to be determined.
Assuntos
Sistema X-AG de Transporte de Aminoácidos/deficiência , Demência/fisiopatologia , Doença dos Neurônios Motores/fisiopatologia , Transtornos Parkinsonianos/fisiopatologia , Sistema X-AG de Transporte de Aminoácidos/fisiologia , Animais , Apolipoproteínas E/genética , Encéfalo/patologia , Demência/genética , Modelos Animais de Doenças , Predisposição Genética para Doença , Camundongos , Doença dos Neurônios Motores/genética , Degeneração Neural/fisiopatologia , Transtornos Parkinsonianos/genéticaRESUMO
Amyotrophic lateral sclerosis-parkinsonism dementia complex (ALS-PDC) is a unique neurodegenerative disease found on the island of Guam. This disease presents as a spectrum of neurological disorders characterized by features of ALS, parkinsonism, dementia, or a combination. The strongest epidemiological link has been to the consumption of the seeds from the cycad plant that purportedly contained a neurotoxin. Mice fed washed cycad flour show signs that mimic ALS-PDC, which include progressive deficits in motor, cognitive, and olfactory functions associated with neuron loss in the spinal cord, nigrostriatal system, cortex, hippocampus, and olfactory bulb. Through a series of chemical extractions of washed cycad flour, we identified steryl glycoside molecules as bioactive molecules that are neurotoxic in culture and in mice. A detailed review of this class of molecule revealed that the molecules are abundant in the environment, particularly in plants and bacteria. Lipid analysis showed that some bacteria that are associated with some forms of neurodegenerative disorders have the capacity to synthesize steryl glycosides. Furthermore, certain steryl glycosides have been found to be a cell stress mediator and may have some immunomodulary effects. We hypothesize that steryl glycosides are putative neurotoxins involved in the etiopathogenesis of several age-related neurodegenerative disorders.