RESUMO
A poorly understood feature of the tauopathies is their very different clinical presentations. The frontotemporal lobar degeneration (FTLD) spectrum is dominated by motor and emotional/psychiatric abnormalities, whereas cognitive and memory deficits are prominent in the early stages of Alzheimer's disease (AD). We report two novel mouse models overexpressing different human tau protein constructs. One is a full-length tau carrying a double mutation [P301S/G335D; line 66 (L66)] and the second is a truncated 3-repeat tau fragment which constitutes the bulk of the PHF core in AD corresponding to residues 296-390 fused with a signal sequence targeting it to the endoplasmic reticulum membrane (line 1; L1). L66 has abundant tau pathology widely distributed throughout the brain, with particularly high counts of affected neurons in hippocampus and entorhinal cortex. The pathology is neuroanatomically static and declines with age. Behaviourally, the model is devoid of a higher cognitive phenotype but presents with sensorimotor impairments and motor learning phenotypes. L1 displays a much weaker histopathological phenotype, but shows evidence of neuroanatomical spread and amplification with age that resembles the Braak staging of AD. Behaviourally, the model has minimal motor deficits but shows severe cognitive impairments affecting particularly the rodent equivalent of episodic memory which progresses with advancing age. In both models, tau aggregation can be dissociated from abnormal phosphorylation. The two models make possible the demonstration of two distinct but nevertheless convergent pathways of tau molecular pathogenesis. L1 appears to be useful for modelling the cognitive impairment of AD, whereas L66 appears to be more useful for modelling the motor features of the FTLD spectrum. Differences in clinical presentation of AD-like and FTLD syndromes are therefore likely to be inherent to the respective underlying tauopathy, and are not dependent on presence or absence of concomitant APP pathology.
Assuntos
Doença de Alzheimer/patologia , Transtornos Cognitivos/patologia , Degeneração Lobar Frontotemporal/patologia , Agregação Patológica de Proteínas/patologia , Proteínas tau/biossíntese , Animais , Cognição/fisiologia , Modelos Animais de Doenças , Feminino , Hipocampo/patologia , Humanos , Masculino , Camundongos , Camundongos Transgênicos , Regiões Promotoras Genéticas , Agregação Patológica de Proteínas/genética , Estrutura Terciária de Proteína , Proteínas tau/genéticaRESUMO
A 13-week-old male intact Poodle mix dog developed an acute onset of vestibular ataxia, tetraparesis, and vomiting. The patient presented ambulatory, tetraparetic, and ataxic with a head tilt to the left and a disconjugate nystagmus (rotary nystagmus with fast phase to the right in right eye and vertical nystagmus in left eye). There were absent postural reactions in the left pelvic and left thoracic limbs and decreased right-sided postural reactions. Magnetic resonance imaging demonstrated an intra-axial mass within the left midcaudal medulla oblongata. On gross dissection, there was a left-sided neoplasm in the medulla oblongata with surrounding hemorrhage. The histologic findings indicated that the mass was a pleomorphic xanthoastrocytoma. This tumor, an uncommon variant of an astrocytoma most often seen in children and young adult humans, has yet to be described in dogs.
Assuntos
Astrocitoma/veterinária , Neoplasias Encefálicas/veterinária , Doenças Vestibulares/veterinária , Animais , Astrocitoma/patologia , Neoplasias Encefálicas/patologia , Cães , Imageamento por Ressonância Magnética/veterinária , Masculino , Bulbo/patologia , Doenças Vestibulares/patologiaRESUMO
Clinical investigations of recombinant human acid alpha-glucosidase for the treatment of Pompe disease often reveal the appearance of therapy-specific antibodies. These antibodies could potentially interfere with recombinant human acid alpha-glucosidase efficacy and induce immunological consequences. Several immunosuppressive agents, including methotrexate, mycophenolate mofetil and cyclosporin A with azathioprine, were evaluated for their potential to induce immune tolerance to recombinant human acid alpha-glucosidase. Methotrexate was the only agent that reduced recombinant human acid alpha-glucosidase-specific antibody responses in acid alpha-glucosidase knock-out mice. A 3-week, low-dose methotrexate regimen controlled recombinant human acid alpha-glucosidase-specific antibody levels throughout 8 months of weekly recombinant human acid alpha-glucosidase treatment. The success of this methotrexate regimen appears to require methotrexate administration within the first 24 h of recombinant human acid alpha-glucosidase treatment. In an attempt to understand the benefit of methotrexate within the first day of recombinant human acid alpha-glucosidase administration, the immune response 24 h following intravenous recombinant human acid alpha-glucosidase treatment was investigated. A consistent expansion of peritoneal B1 B cells was observed. Control over this B1 B cell response may be part of the complex mechanism of action of methotrexate-induced immune tolerance.
Assuntos
Doença de Depósito de Glicogênio Tipo II/tratamento farmacológico , Tolerância Imunológica/efeitos dos fármacos , Imunossupressores/farmacologia , Metotrexato/farmacologia , alfa-Glucosidases/imunologia , Animais , Modelos Animais de Doenças , Relação Dose-Resposta Imunológica , Esquema de Medicação , Avaliação Pré-Clínica de Medicamentos/métodos , Feminino , Doença de Depósito de Glicogênio Tipo II/imunologia , Imunoglobulina G/biossíntese , Imunossupressores/administração & dosagem , Injeções Intraperitoneais , Injeções Intravenosas , Masculino , Metotrexato/administração & dosagem , Camundongos , Camundongos Knockout , Proteínas Recombinantes/imunologia , Proteínas Recombinantes/uso terapêutico , alfa-Glucosidases/administração & dosagem , alfa-Glucosidases/uso terapêuticoRESUMO
This study describes the properties of the two recombinantly expressed polypeptide chains of Fel d I, the major allergen produced by the domestic cat (Felis domesticus). An inframe linker encoding polyhistidine has been added to the 5' ends of the Fel d I chains 1 and 2 cDNAs to facilitate purification using Ni2+ ion affinity chromatography. This method provides high yields in a single step of rchain 1 and rchain 2 of Fel d I with a > 90% level of purity. Polymerase chain reaction (PCR) methods were used to introduce a thrombin cleavage site (LVPR decreases GS) at the N-terminus of both chains. Thrombin cleavage of rchain 1 and rchain 2 followed by HPLC purification of the cleavage products allowed the isolation of each recombinant chain with only two additional residuals (GS) at the N-terminus of the native sequence. Amino acid sequencing analysis of the N-terminus and mass spectrometry of these polypeptides demonstrated that they are highly pure and full-length. Direct ELISA assays showed that IgE from cat-allergic patients binds to both rchain 1 and rchain 2 of Fel d I, demonstrating that both these chains contribute to the allergenicity of this heterodimeric protein. An examination of the reactivity of T cells derived from cat-allergic patients revealed that both polypeptide chains contribute to the T cell response to this allergen. Consequently, it is concluded that the immunological response to Fel d I is composed of a reaction at both the B and T cell level to each of the two chains that constitute the native allergen.
Assuntos
Alérgenos/imunologia , Gatos/imunologia , Glicoproteínas , Hipersensibilidade Imediata/imunologia , Imunoglobulina E/imunologia , Linfócitos T/imunologia , Alérgenos/biossíntese , Alérgenos/química , Alérgenos/isolamento & purificação , Sequência de Aminoácidos , Animais , Células Apresentadoras de Antígenos , Sequência de Bases , Cromatografia de Afinidade , Cromatografia Líquida de Alta Pressão , Relação Dose-Resposta Imunológica , Ensaio de Imunoadsorção Enzimática , Escherichia coli/genética , Humanos , Ativação Linfocitária/imunologia , Dados de Sequência Molecular , Sondas de Oligonucleotídeos , Reação em Cadeia da Polimerase , Proteínas Recombinantes/biossíntese , Proteínas Recombinantes/química , Proteínas Recombinantes/imunologia , Proteínas Recombinantes/isolamento & purificação , Trombina/metabolismo , Transformação GenéticaRESUMO
BACKGROUND: In 68% of foodborne disease outbreaks, no etiologic pathogen is identified. In two-thirds of outbreaks with no identified etiology, no stool specimens are submitted for testing. METHODS: From April 2001 to March 2003, we pilot-tested use of prepackaged, self-contained stool specimen collection kits in 3 states, delivered to and from patients by courier or mail, to improve rates of specimen collection in the outbreak setting. Specimens were tested for bacterial and viral pathogens at health department laboratories, and results were correlated with epidemiological investigation data. RESULTS: Specimens were returned by > or =1 person in 52 (96%) of 54 outbreaks in which kits were deployed; in total, 263 (76%) of 347 persons who received kits returned specimens. Resolution of symptoms was the most commonly cited reason for nonsubmission of kits. An etiology was confirmed in 37 (71%) of 52 outbreaks with specimens returned; 28 (76%) were attributable to norovirus, and 9 (24%) were attributed to bacterial pathogens. Stool kits were well received and cost an average of approximately 43 dollars per specimen returned. CONCLUSIONS: In two-thirds of foodborne disease outbreaks in which delivered stool collection kits were successfully deployed, an etiologic organism was identified. Delivery of kits to and from patients to improve rates of stool collection in outbreaks in which specimens might otherwise not be submitted could substantially reduce the number of outbreaks with an unknown etiology.
Assuntos
Surtos de Doenças , Fezes/microbiologia , Microbiologia de Alimentos , Infecções/diagnóstico , Infecções/microbiologia , Kit de Reagentes para Diagnóstico , Humanos , Projetos Piloto , Manejo de EspécimesRESUMO
Immunization with acetylcholine receptor (AChR) causes experimental myasthenia gravis (EMG). The s.c. administration to C57B1/6 mice of synthetic AChR CD4+ epitopes, before and during AChR immunization, reduced the epitope-specific CD4+ responses and the anti-AChR Ab synthesis, and prevented EMG. The s.c. administration of solubilized AChR had effects similar to those of peptide treatment. Sham-tolerized mice had only Th1 anti-AChR cells, whereas peptide-treated mice had also Th2 cells, and Th2-induced anti-peptide Ab. Established EMG was not affected by s.c. peptide treatment, whereas it worsened after s.c. administration of solubilized AChR.
Assuntos
Epitopos/imunologia , Miastenia Gravis/imunologia , Miastenia Gravis/prevenção & controle , Receptores Colinérgicos/imunologia , Animais , Autoanticorpos/biossíntese , Autoanticorpos/imunologia , Linfócitos T CD4-Positivos/citologia , Linfócitos T CD4-Positivos/imunologia , Divisão Celular/efeitos dos fármacos , Divisão Celular/imunologia , Modelos Animais de Doenças , Epitopos/farmacologia , Tolerância Imunológica/imunologia , Imunização , Injeções Subcutâneas , Camundongos , Camundongos Endogâmicos , Fragmentos de Peptídeos/imunologia , Fragmentos de Peptídeos/farmacologia , Solubilidade , Células Th2/imunologia , TorpedoRESUMO
Neuropathologic assessment of chemically induced developmental alterations in the nervous system for regulatory purposes is a multifactorial, complex process. This calls for careful qualitative and quantitative morphologic study of numerous brains at several developmental stages in rats. Quantitative evaluation may include such basic methods as determination of brain weight and dimensions as well as the progressively more complex approaches of linear, areal, or stereologic measurement of brain sections. Histologic evaluation employs routine stains (such as hematoxylin and eosin), which can be complemented by a variety of special and immunohistochemical procedures. These brain studies are augmented by morphologic assessment of selected peripheral nervous system structures. Studies of this nature require a high level of technical skill as well as special training on the part of the pathologist. The pathologist should have knowledge of normal microscopic neuroanatomy/neuronal circuitry and an understanding of basic principles of developmental neurobiology, such as familiarity with the patterns of physiologic or programmed cell de
Assuntos
Comportamento Animal/efeitos dos fármacos , Encéfalo/efeitos dos fármacos , Encéfalo/crescimento & desenvolvimento , Sistema Nervoso Periférico/efeitos dos fármacos , Sistema Nervoso Periférico/crescimento & desenvolvimento , Xenobióticos/efeitos adversos , Animais , Biometria , Humanos , Ratos , Medição de Risco , Manejo de Espécimes , Fixação de TecidosRESUMO
Pregnant Sprague-Dawley rats were given chlorpyrifos (O:, O-diethyl-O:-[3,5,6-trichloro-2-pyridinyl] phosphorothioate; CPF) in corn oil by gavage from gestation day 6 (GD 6) through lactation day 10 (LD 10) at dosages of 0, 0.3, 1, or 5 mg/kg/day in a developmental neurotoxicity study that conformed to U.S. Environmental Protection Agency 1991 guidelines. GD 0 was the day when evidence of mating was observed and postnatal day 0 (PND 0) was the day of birth. Toxicity was limited to the highest dosage level (5 mg/kg/day) and, in the dams, consisted of muscle fasciculation, hyperpnea, and hyperreactivity. A nonsignificant overall trend toward weight gain and feed consumption was also observed in the high-dosage dams, with a statistically significant Group x Time interaction for reduced weight gain in the 5-mg/kg/day group near the end of gestation. Although many developmental indices were normal, pups from high-dosage dams had increased mortality soon after birth, gained weight more slowly than controls, and had several indications of slightly delayed maturation. The early deaths and delayed maturation were attributed to maternal toxicity, though a possible contributing role of direct pup toxicity in delayed development cannot be eliminated. In spite of the apparent delay in physical development, high-dosage pups tested just after weaning had normal learning and memory as tested on a T-maze spatial delayed-alternation task. Habituation, a primitive form of learning, was tested in 2 tasks (motor activity and auditory startle) and was not affected. No overt effects were noted in either dams or pups at 1 or 0.3 mg/kg/day. Based on these data, chlorpyrifos produced maternal and developmental toxicity in the 5-mg/kg/day-dosage group. There was no evidence of selective developmental neurotoxicity following exposure to chlorpyrifos.
Assuntos
Encéfalo/efeitos dos fármacos , Clorpirifos/toxicidade , Inseticidas/toxicidade , Malformações do Sistema Nervoso/induzido quimicamente , Efeitos Tardios da Exposição Pré-Natal , Administração Oral , Animais , Animais Recém-Nascidos/crescimento & desenvolvimento , Animais Lactentes/crescimento & desenvolvimento , Comportamento Animal/efeitos dos fármacos , Peso Corporal/efeitos dos fármacos , Encéfalo/anormalidades , Clorpirifos/administração & dosagem , Colinesterases/sangue , Cognição/efeitos dos fármacos , Feminino , Inseticidas/administração & dosagem , Masculino , Exposição Materna , Aprendizagem em Labirinto/efeitos dos fármacos , Memória/efeitos dos fármacos , Atividade Motora/efeitos dos fármacos , Malformações do Sistema Nervoso/patologia , Tamanho do Órgão/efeitos dos fármacos , Gravidez , Ratos , Ratos Sprague-Dawley , Reflexo de Sobressalto/efeitos dos fármacos , Percepção Espacial/efeitos dos fármacos , Testes de ToxicidadeRESUMO
The potential for neurotoxic effects was evaluated in rat off-spring after exposure in utero and/or during the neonatal period to a recombinant subunit vaccine of gp120 prepared from the MN strain of HIV-1 (MN rgp 120/HIV-1). Thirty pregnant female rats were given MN rgp120/HIV-1 with alum adjuvant, and 30 rats were given vehicle, once every 3 days from Day 1 of presumed gestation until parturition. One pup/sex/litter from treated and control group dams were given a daily subcutaneous injection, from Day 1 through Day 22 postpartum (PP) of vehicle, MN rgp120/HIV-1, MN rgp120/HIV-1 with alum, or MN rgp120/HIV-1 with QS-21 adjuvant. Neurobehavioral and physical development were evaluated (preweaning reflex and development, sexual maturation, motor activity, acoustic startle, passive avoidance, functional observational battery, and water M-maze testing), and tissues were processed for anatomical examination (whole and regional brain weights, and neuropathology). Administration of MN rgp120/HIV-1, with or without adjuvant, to pups did not cause any persistent effect on any parameter evaluated. Neurohistological examination did not reveal any pathological effects related to treatment. Thus, MN rgp120/HIV-1 alone or formulated as a vaccine does not cause neurotoxicity or developmental toxicity in neonatal rats after exposure in utero and/or during the neonatal period.
Assuntos
Vacinas contra a AIDS/toxicidade , Encéfalo/efeitos dos fármacos , Desenvolvimento Embrionário e Fetal/efeitos dos fármacos , Proteína gp120 do Envelope de HIV/imunologia , Efeitos Tardios da Exposição Pré-Natal , Animais , Animais Recém-Nascidos , Aprendizagem da Esquiva/efeitos dos fármacos , Comportamento Animal/efeitos dos fármacos , Peso Corporal/efeitos dos fármacos , Encéfalo/embriologia , Encéfalo/fisiopatologia , Feminino , Injeções Subcutâneas , Aprendizagem em Labirinto/efeitos dos fármacos , Leite/imunologia , Atividade Motora/efeitos dos fármacos , Gravidez , Ratos , Ratos Sprague-Dawley , Maturidade Sexual/efeitos dos fármacos , Vacinas Sintéticas/toxicidadeRESUMO
We tested the hypothesis that fentanyl would worsen ischemia-induced brain damage. In two sequential protocols forty rats were physiologically monitored and controlled. In protocol 1, rats were randomized (n=10/group) to 30 min of control (N2O plus 0.4% halothane), low dose fentanyl (loading dose [LD] 50 micrograms kg-1, maintenance dose [MD] 2 micrograms kg-1 min-1), or high-dose fentanyl (LD 800 micrograms kg-1, MD 32 micrograms kg-1 min-1). After 15 min of fentanyl or sham infusion trimethaphan 0.5 mg was given i.v. and 3 min later bilateral carotid artery occlusion and blood withdrawal-induced hypotension were maintained for 12 min. At 18 h postischemia rats underwent cerebral perfusion fixation. Brain areas were graded from 0 (normal) to 5. In addition to analysis of specific regions, neuropathologic scores were also summated over all brain regions and analyzed to compute a summed neuropathologic score. In protocol 2, five control and five high-dose fentanyl rats were treated identically except that post-ischemic oxygenation was maintained for 6 h and cerebral perfusion-fixation was performed 6 h post-ischemia. Only the caudate/putamen was examined in protocol 2. Fentanyl worsened lesions in both fentanyl groups' summed neuropathologic scores (P=0.002) in protocol 1 and specifically, in the caudate/putamen (P<0.01) in both protocols. Fentanyl in both high and low doses can exacerbate incomplete forebrain ischemia in rats.
Assuntos
Analgésicos Opioides/toxicidade , Isquemia Encefálica/induzido quimicamente , Fentanila/toxicidade , Neurotoxinas/toxicidade , Análise de Variância , Animais , Relação Dose-Resposta a Droga , Masculino , Ratos , Ratos Sprague-Dawley , Resultado do TratamentoRESUMO
We tested the hypothesis that hyperglycemic exacerbation of incomplete forebrain ischemia is mediated by increased extracellular dopamine levels. Normoglycemic and hyperglycemic Sprague-Dawley rats (eight each) with previously placed coaxial striatal microdialysis probes underwent 12 min of forebrain ischemia produced by bilateral carotid artery occlusion and trimethaphan-induced hypotension. Microdialysis was performed before, during, and for 6 h after ischemia, then perfusion-fixation was performed. Hyperglycemic rats had more severe postischemic damage in the caudate-putamen, neocortex, and hippocampus. Extracellular striatal dopamine levels were increased by ischemia, but were unaffected by hyperglycemia. These data show that hyperglycemic exacerbation of ischemic striatal damage does not depend on elevated extracellular dopamine levels.
Assuntos
Isquemia Encefálica/metabolismo , Dopamina/metabolismo , Espaço Extracelular/metabolismo , Hiperglicemia/metabolismo , Neostriado/metabolismo , Animais , Glicemia/metabolismo , Encéfalo/patologia , Isquemia Encefálica/patologia , Artérias Carótidas/fisiologia , Hiperglicemia/patologia , Hipotensão/induzido quimicamente , Hipotensão/metabolismo , Masculino , Microdiálise , Neostriado/patologia , Ratos , Ratos Sprague-Dawley , TrimetafanoRESUMO
Groups of F344 rats of each sex were exposed to either ethylene oxide (ETO) vapor (concentrations of 100, 33 or 10 ppm) or to room air for 6 hours daily, 5 days per week, for up to 2 years. Three representative sections of the brain from each rat were evaluated. Twenty-three primary brain tumors were found, two of which were in control animals. Increased numbers of brain tumors were seen in 100 ppm and 33 ppm ETO exposed male and female rats. Significant trend analyses were found for both males and females, indicating that, under the conditions of this study, ETO exposure above 10 ppm was related to the development of these brain tumors.
Assuntos
Neoplasias Encefálicas/induzido quimicamente , Óxido de Etileno/toxicidade , Poluentes Atmosféricos/toxicidade , Animais , Encéfalo/patologia , Neoplasias Encefálicas/patologia , Feminino , Glioma/induzido quimicamente , Doenças Linfáticas/induzido quimicamente , Linfoma Difuso de Grandes Células B/induzido quimicamente , Masculino , Ratos , Ratos Endogâmicos F344 , Fatores SexuaisRESUMO
Pigeons repeatedly exposed to sublethal doses of methylmercury (5-10 mg Hg/kg/wk, po, for 34-77 days) exhibited marked behavioral changes that were accompanied by only minor evidence of neuropathologic changes at the light microscopic level. Accuracy and rate of pecking for grain declined while food intake remained unchanged. Methylmercury produced permanent changes in posture and in motor coordination. The regional distribution of methylmercury within the nervous system was poorly correlated with the distribution of pathologic changes. Overt behavioral signs appeared after the brain accumulated more than about 12 to 16 ppm Hg. Data with pigeons support earlier evidence that the dose-response function for methylmercury is modulated by dose rate and duration of exposure, since the pattern of blood and tissue distribution of Hg is established in advance of the appearance of signs. The pigeon is more sensitive to methylmercury than are mice and rats, but less sensitive than primates.
Assuntos
Encefalopatias/induzido quimicamente , Compostos de Metilmercúrio/toxicidade , Animais , Comportamento Animal/efeitos dos fármacos , Encéfalo/metabolismo , Columbidae , Feminino , Cinética , Masculino , Radioisótopos de Mercúrio , Camundongos , Camundongos Endogâmicos BALB C , Fatores de TempoRESUMO
n-Butyl acetate, a common industrial solvent, was selected by the US EPA as a chemical of concern for neurotoxicity as part of the Multisubstance Rule for the Testing of Neurotoxicity. The neurotoxic potential of n-butyl acetate was investigated in Sprague-Dawley rats using a functional observational battery, motor activity, neurohistopathology, and schedule-controlled operant behavior (SCOB) as indicators of neurotoxicity. Animals were exposed to concentrations of 0, 500, 1500, or 3000 ppm of n-butyl acetate for 6 hours per day for 65 exposures over 14 weeks. Functional observational battery and motor activity values for ad libitum-fed male and female rats were measured during Weeks -1, 4, 8, and 13. SCOB testing of food-restricted animals, using a multiple fixed ratio/fixed interval schedule, was conducted daily prior to each exposure to maintain the operant behavior; the data from Weeks -1, 4, 8, and 13 were evaluated for evidence of neurotoxicity. Transient signs of sedation and hypoactivity were observed only during exposure to the 1500 and 3000 ppm concentrations. The only signs of systemic toxicity were reduced body weights for the 3000 ppm ad libitum-fed groups and occasionally for the female 1500 ppm ad libitum-fed group. No evidence of neurotoxicity was seen during the functional observational battery examinations. Motor activity for the 3000 ppm male group was significantly (p < or = 0.05) higher than for the control group only during Week 4. No significant differences were observed among groups for Weeks 8 and 13. No significant differences in motor activity values were observed for female rats. No significant differences were seen in operant behavior at any test vapor concentration. Microscopic evaluations of sections from the brain, spinal cord (cervical and lumbar regions), dorsal and ventral spinal roots, dorsal root ganglia, sciatic nerve, and tibial nerve of animals in the control and 3000 ppm groups did not indicate any treatment-related effects. In conclusion, there was no evidence of cumulative neurotoxicity based on the functional observational battery, motor activity, neurohistopathology, and schedule-controlled operant behavior endpoints. The data presented here are relevant to the neurotoxicity risk assessment of n-butanol due to the rapid hydrolysis of n-butyl acetate in vivo.
Assuntos
Acetatos/toxicidade , Neurotoxinas/toxicidade , Animais , Peso Corporal/efeitos dos fármacos , Sistema Nervoso Central/efeitos dos fármacos , Sistema Nervoso Central/patologia , Condicionamento Operante/efeitos dos fármacos , Estudos de Avaliação como Assunto , Feminino , Masculino , Atividade Motora/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Esquema de Reforço , VolatilizaçãoRESUMO
We hypothesized that blockade of synthesis or release of several categories of neurotransmitters would ameliorate opioid neurotoxicity. Rats were randomly assigned to one of six groups in two sequential protocols: vesamicol (VES, n = 10), alpha-fluoromethylhistidine (FMH, n = 10), reserpine (RES, n = 10), BW1003C87 (BW, n = 7), lamotrigine (LAM, n = 10), or one of two control groups (CON, n = 19). Physiologically controlled rats received fentanyl (fen) i.v., loading dose 800 micrograms kg-1 followed by maintenance dose 32 micrograms kg-1 min-1 for 2 h. Drug dosing: CON, isovolemic (between rats) 0.9% saline i.v.; BW, 20 mg kg-1 i.v. 15 min pre-fen; LAM, 16 mg kg-1 i.v. 30 min pre-fen; VES, 2.5 mg kg-1 i.p. 60 min and 30 min pre-fen then infused 3.75 mg kg-1 during fen; FMH, 20 mg kg-1 i.p. 2 h pre-fen; RES, 0.75 mg kg-1 i.p. 18 h pre-fen. Seven days later all rats underwent cerebral perfusion fixation, followed by histologic grading (0-5, 0 = normal). Pathological data was analyzed by Wilcoxen's Signed rank test (two-tailed) for pathologic scores summated across all brain areas (overall severity score) and for scores of areas previously associated with opioid neurotoxicity. Compared to CON, overall severity was decreased by RES (p = 0.05) with an effect suggested by VES (p = 0.10). Compared to CON, lesions were decreased: (a) in the amygdala with VES (p = 0.03) and RES (p = 0.05) with a trend suggested by BW (p = 0.06); (b) in the subiculum by VES (p = 0.02) and RES (p = 0.008) with a trend suggested by FMH (p = 0.06); and (c) in the entorhinal cortex by VES (p = 0.004) and RES (p = 0.008) with a trend suggested by FMH (p = 0.07). The data indicate that brain acetylcholine and catecholamines contribute to opioid neurotoxicity, and suggest a possible role of glutamate and histamine in opioid neurotoxicity.
Assuntos
Inibidores da Captação Adrenérgica/farmacologia , Analgésicos Opioides/farmacologia , Encéfalo/efeitos dos fármacos , Antagonistas de Aminoácidos Excitatórios/farmacologia , Fármacos Neuromusculares Despolarizantes/farmacologia , Fármacos Neuroprotetores/farmacologia , Animais , Pressão Sanguínea/efeitos dos fármacos , Pressão Sanguínea/fisiologia , Temperatura Corporal/efeitos dos fármacos , Temperatura Corporal/fisiologia , Encéfalo/patologia , Fentanila/farmacologia , Lamotrigina , Masculino , Piperidinas/farmacologia , Pirimidinas/farmacologia , Ratos , Ratos Sprague-Dawley , Reserpina/farmacologia , Triazinas/farmacologiaRESUMO
Increased frequencies of primary brain tumours were seen in male and female F-344 rats exposed to 100 or 33 ppm ethylene oxide (EO) vapour (for 6 hr daily on 5 days/wk for up to 2 yr) but no such increase was seen in rats similarly exposed to 10 ppm EO. The tumours that were seen (glial-cell tumours, granular-cell tumours and malignant reticuloses) were similar in appearance to those that develop spontaneously in F-344 rats, but the tumours associated with EO exposure at levels of 100 or 33 ppm were larger, and in at least six cases were thought to be the primary cause of death. Only two of the 23 tumours seen microscopically were detected by gross examination at necropsy, and brain weights were of minimal value in predicting the presence of tumours. Only three animals demonstrated abnormal neurological signs. These findings point to the need for thorough microscopic examination of the brains of rodents in chronic studies.
Assuntos
Neoplasias Encefálicas/induzido quimicamente , Óxido de Etileno , Ratos Endogâmicos F344 , Ratos Endogâmicos , Fatores Etários , Animais , Encéfalo/patologia , Neoplasias Encefálicas/patologia , Feminino , Masculino , Tamanho do Órgão , RatosRESUMO
Ethylenediamine dihydrochloride (EDA.2HCl) was incorporated into the diet and fed to Fischer 344 rats for 2 years at target doses of 0, 0.02, 0.10 or 0.35 g/kg/day (equivalent to 0.009, 0.045 and 0.158 g free EDA/kg/day). Two separate untreated control groups were used. Interim sacrifices were at 6, 12 and 18 months and the terminal sacrifice was at 24 months. Under the conditions of this study, EDA.2HCl was not carcinogenic in the Fischer 344 rat. Most toxic responses were observed at the 12-month sacrifice and thereafter. Reductions in mean body weight gain were observed in high dose group male rats throughout most of the study and in the high dose group of female rats after approximately 18 months. Conversely, there was a slight increase in the mean body weight gain for the medium level female rats from about day 21 until 21 months that was of equivocal biological significance. Increased mortality was observed in the high dose group of both sexes and the mid dose group of female rats. The cause of the decreased survival was unclear, but may have been related to the enhancement of background degenerative lesions such as chronic nephropathy. Throughout the study, male rats from the high dose group had decreased erythrocyte counts, haemoglobin concentration and haematocrit. The cause and biological significance of the haematological changes were unknown. Increased water consumption was observed in the high dose group of both sexes during the latter half of the study. Increased urine volume with concurrent decreased urine specific gravity was generally observed in the high dose group of both sexes in the last half of the study and suggested a possible alteration in kidney function. Altered urine volume and specific gravity persisted to termination in female rats only. Slight increases in absolute and relative kidney weights were also observed in the high dose group of female rats during the latter half of the study. Hepatocellular pleomorphism was observed in the high dose group of both sexes, especially the female rats, and may have contributed to increased mean liver weights observed primarily in female rats from the high dose group. Hepatocellular pleomorphism was first observed in female rats at 12 months but was not observed in male rats until the final sacrifice. Rhinitis and tracheitis were observed with greater frequency in the high dose group of male rats at 12, 18 and 24 months and in high dose group female rats at 18 months. At 24 months, rhinitis, but not tracheitis, persisted at a significantly greater frequency in high dose group female rats. The apparent no-observable-effect level (NOEL) of this study was at the lowest dose level, 0.02 g/kg/day (equivalent to 9 mg EDA/kg/day).
Assuntos
Carcinógenos/toxicidade , Etilenodiaminas/toxicidade , Animais , Contagem de Células Sanguíneas , Peso Corporal/efeitos dos fármacos , Dieta , Ingestão de Líquidos/efeitos dos fármacos , Feminino , Fígado/patologia , Masculino , Tamanho do Órgão/efeitos dos fármacos , Ratos , Ratos Endogâmicos F344 , Urodinâmica/efeitos dos fármacosRESUMO
Two inhalation studies were conducted to evaluate the possible subchronic and developmental toxic effects of n-butyl propionate. In the subchronic study, Sprague-Dawley rats (15/sex/group) were exposed to 0, 250, 750, or 1500 ppm vapor for 6 h/d, 5 d/wk for 13 wk. Five of the rats per sex per group were held after the final exposure for an 8-wk recovery period. Standard parameters of subchronic toxicity were measured throughout the study, and at the end of exposure and recovery periods, necropsies were performed, organs weighed, and tissues processed for microscopic examination. Exposure did not produce marked treatment-related deaths or adversely affect clinical signs, hematology, clinical chemistries, organ weights, or the histology of major visceral organs. The only systemic toxic effects were significant decreases in body weight, body weight gain, and feed consumption that occurred in 1500 ppm group rats. Morphologic changes were limited to the nasal cavity as evidenced by a concentration-related increased incidence and severity of olfactory epithelium degeneration in rats of the 750 and 1500 ppm groups. These degenerative microscopic alterations were primarily confined to the olfactory epithelium within the dorsal portion of the medial meatus, with lesser involvement of the olfactory mucosae overlying the tips of some of the adjacent ethmoturbinates. Both the systemic and nasal cavity effects appeared reversible after exposure ceased. In the developmental toxicity study, pregnant Sprague-Dawley rats (24/group) were exposed to 0, 500, 1000, or 2000 ppm vapor for 6 h/d on gestation d 6-15 and sacrificed on gestation d 20. All treatment-group dams exhibited significant reductions in body weight, body weight gain, and feed consumption. Gestational parameters were equivalent across all groups and there were no treatment-related developmental or teratogenic effects. The no-observed-adverse effects levels (NOAELs) determined for nbutyl propionate were 250 ppm for subchronic toxicity (based on the olfactory epithelium degeneration) and 22000 ppm for developmental toxicity (no developmental effects at top dose tested). Under the conditions of this study, a NOAEL was not determined for maternal toxicity.
Assuntos
Propionatos/toxicidade , Reprodução/efeitos dos fármacos , Administração por Inalação , Animais , Análise Química do Sangue , Peso Corporal/efeitos dos fármacos , Anormalidades Congênitas/etiologia , Ingestão de Alimentos/efeitos dos fármacos , Desenvolvimento Embrionário e Fetal/efeitos dos fármacos , Feminino , Crescimento/efeitos dos fármacos , Masculino , Exposição Materna/efeitos adversos , Mucosa Nasal/efeitos dos fármacos , Mucosa Nasal/patologia , Gravidez , Propionatos/administração & dosagem , Ratos , Ratos Sprague-Dawley , SolventesRESUMO
1. Male and female Fischer 344 rats were exposed to 2,4-pentanedione (2,4-PD) vapour acutely (4 h) at 1265 or 1811 ppm, or for 6 h day-1, 5 days a week for 14 weeks to 0, 101, 307 or 650 ppm. 2. Mortality occurred during or within a few hours of the acute exposures (10% at 1265 ppm; 70% at 1811 ppm). No animal had gross or microscopic brain lesions. 3. All female rats (20) and 10 of 30 male rats exposed to 650 ppm 2,4-PD vapour died by the 38th study day (29 exposures); there were no subsequent male deaths. Twenty-five of the 30 animals that died, and seven of the 15 males that survived, had light microscopical evidence of degenerative lesions, principally within the caudate/putamen nuclei, nuclei of the cerebellar medulla, and vestibular nuclei. Less frequently involved, in animals that died, were various regions of the cerebral cortex. The early histopathological lesions, seen from the 16th study day (12 exposures) to the 38th study day (28 exposures) were characterised by malacia. When present, lesions in male rats surviving the 14-weeks of 650 ppm 2, 4-PD exposure were characterised by malacia and gliosis. No peripheral nerve lesions were seen by light or transmission electron microscopy. 4. Neither mortality nor neuropathology were seen in rats subchronically exposed to 101 or 307 ppm, 2,4-PD vapour.
Assuntos
Doenças do Sistema Nervoso/induzido quimicamente , Pentanonas/administração & dosagem , Pentanonas/toxicidade , Administração por Inalação , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/patologia , Feminino , Masculino , Necrose/induzido quimicamente , Tamanho do Órgão/efeitos dos fármacos , Ratos , Ratos Endogâmicos F344 , Taxa de SobrevidaRESUMO
A hamster-associated epizootic of lymphocytic choriomeningitis (LCM) virus infection in medical center personnel at the University of Rochester in 1973 necessitated prompt termination of the Syrain hamster colony. Necropsies were performed on 130 hamsters, blood speciments were obtained from 60 for serotest, and viral isolation procedures were done on 47. Active virus infection, as shown by virus isolation, was associated with the presence of lymphoreticular infiltrate in liver and kidney. Intraabdominal lymphoma was seen only in groups of hamsters from which LCM virus was isolated, but LCM virus was not isolated from many of the hamsters with lymphoma. Although frequency of intraabdominal lymphoma could be markedly increased in LCM-positive hamsters treated with 7,12-dimethylbenz(a)anthracene, lymphoma was not induced in LCM-negative hamsters with this carcinogen.