RESUMEN
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.
Asunto(s)
Enfermedad de Alzheimer/patología , Trastornos del Conocimiento/patología , Degeneración Lobar Frontotemporal/patología , Agregación Patológica de Proteínas/patología , Proteínas tau/biosíntesis , Animales , Cognición/fisiología , Modelos Animales de Enfermedad , Femenino , Hipocampo/patología , Humanos , Masculino , Ratones , Ratones Transgénicos , Regiones Promotoras Genéticas , Agregación Patológica de Proteínas/genética , Estructura Terciaria de Proteína , Proteínas tau/genéticaRESUMEN
The objective of this study is to determine the influence of aluminum sorption on a calcium-polygalacturonate (Ca-PG) network used as a soil-root interface model. The Ca-PG network is exposed to aluminum solutions at different concentrations (25-800 microM) at pH 3.50. High concentrations lead to a release of calcium (80%) and aluminum becomes the predominant reticulating cation of the polygalacturonic chains. The FTIR spectra show how aluminum sorption induces shifts of the characteristic bands of carbohydrates in the spectral regions of 1700-1400 and 1200-800 cm(-1), which are enhanced by decreasing intensities. This might be induced by a weakening of the metal-PG complex through conformational variations of the structure. Scanning electron micrographs also show a collapse of the fibrillar structure of Ca-PG that is due to aluminum sorption. This structural rearrangement suggests that the soil-root interface could modify its functionality, affecting the transport of metal ions (nutrients) across the interface and consequently through the cell membranes.
Asunto(s)
Aluminio/química , Calcio/química , Modelos Biológicos , Pectinas/química , Espectroscopía Infrarroja por Transformada de FourierRESUMEN
Because opioid and cannabinoid systems have been reported to interact in the modulation of addictive behaviour, this study was aimed at investigating the ability of cannabinoid agents to reinstate or prevent heroin-seeking behaviour after a prolonged period of extinction. In rats previously trained to self-administer heroin intravenously, non-contingent non-reinforced priming administrations of heroin and cannabinoids were presented after long-term extinction, and lever pressing following injections was observed. Results showed that: (i) intravenous priming infusions of heroin (0.1 and 0.2 mg/kg) lead to reinstatement of drug-seeking behaviour; (ii) intraperitoneal priming injections of the central cannabinoid receptor agonists R-(+)-(2,3-dihydro-5-methyl-3-[(4-morpholinyl)methyl]pyrol[1,2,3-de]-1,4-benzoxazinyl) (1-naphthalenyl)methanonemesylate (WIN 55,212-2, 0.15 and 0.3 mg/kg) and (-)-cis-3-[2-hydroxy-4(1,1-dimethyl-heptyl)phenyl]-trans-4-(3-hydroxypropyl) cyclohexanol (CP 55,940, 0.05 and 0.1 mg/kg), but not delta9-tetrahydrocannabinol (delta9-THC, 0.1-1.0 mg/kg), effectively restored heroin-seeking behaviour; (iii) intraperitoneal priming injection of the central cannabinoid receptor antagonist N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichloro-phenyl)4-methyl-1H-pyrazole-3-carboxamide (SR 141716A, 0.3 mg/kg) did not reinstate responding, but (iv) completely prevented heroin-induced reinstatement of drug-seeking behaviour. Moreover, heroin-seeking behaviour was still present for a few days following cannabinoid primings, indicating a long-lasting effect of cannabinoids on responding for heroin. These findings indicate that relapse to heroin after an extended drug-free period is triggered by cannabinoid agonists and that SR 141716A prevents drug-seeking behaviour, suggesting that the use of the cannabinoid antagonist could have some therapeutic benefits in heroin-induced relapse.
Asunto(s)
Extinción Psicológica/fisiología , Dependencia de Heroína/fisiopatología , Heroína/farmacología , Narcóticos/farmacología , Receptores de Droga/metabolismo , Animales , Conducta Animal/efectos de los fármacos , Cannabinoides/farmacología , Condicionamiento Operante/efectos de los fármacos , Heroína/administración & dosificación , Masculino , Narcóticos/administración & dosificación , Ratas , Receptores de Cannabinoides , Receptores de Droga/agonistas , Receptores de Droga/antagonistas & inhibidores , AutoadministraciónRESUMEN
gamma-Hydroxybutyric acid (GHB) is a widely used recreational drug known to exert positive reinforcing effects in animals and humans. The GABA(B) receptor agonist baclofen has been proved to possess antimotivational effect and to inhibit alcohol, cocaine, heroin and nicotine intake. In the present study we evaluated the effect of baclofen on i.v. self-administration of GHB in drug-naive mice under a fixed-ratio (FR-1) schedule of reinforcement and nose-poking-like response as operandum. Results show that baclofen was able to completely prevent GHB seeking behaviour, decreasing the rate of responding to basal values, without showing any reinforcing properties when made contingent on nose-poking response. Our findings demonstrate that baclofen antagonises GHB i.v. self-administration, supporting an important role for the GABA(B) receptor in reward-related mechanisms underlying addictive behaviour.
Asunto(s)
Baclofeno/farmacología , Agonistas del GABA/farmacología , Hidroxibutiratos/administración & dosificación , Refuerzo en Psicología , Autoadministración , Animales , Baclofeno/uso terapéutico , Conducta Adictiva/tratamiento farmacológico , Conducta Adictiva/psicología , Agonistas del GABA/uso terapéutico , Inyecciones Intravenosas , Masculino , Ratones , Receptores de GABA-B/fisiología , Autoadministración/psicologíaRESUMEN
The interaction between parathion and beta-cyclodextrin was investigated by Molecular Dynamics. Several in vacuo trajectories were calculated for the system imposing a 1:1 stoichiometry. The influence of the solvent and temperature was considered. The results account for the formation of adducts which are stable at room temperature and involve mainly the nitrophenoxy group of the guest molecules which interacts with the hydrophobic cavity of the host by van der Waals forces.
Asunto(s)
Ciclodextrinas/química , Insecticidas/química , Paratión/química , beta-Ciclodextrinas , Sitios de Unión , Estabilidad de Medicamentos , Modelos Moleculares , Solventes , Temperatura , Termodinámica , Agua/químicaRESUMEN
Partially esterified polygalacturonic acid is the main component of pectin in higher plants. The carboxylic groups and their methyl esters markedly affect the ability of the pectin molecules to bind oppositely charged ions and to form gels. In order to make a contribution to the understanding of the mechanisms which regulate the ionic transfer at the soil-root interface and in the apoplast, we report the results of a set of molecular dynamics experiments in which the interactions of four fully deprotonated fragments of polygalacturonic acid, each counting 12 units, 300 water molecules and 48 or 24 Na+ and Ca2+ ions were studied. We observed the formation of Ca2+ bridges between the polygalacturonate chains. The forces driving the aggregation processes are characterized by the formation of strong coulombic interactions between the metal ions and the carboxylate groups. The results are consistent with experiment evidence of the formation of Ca-polygalacturonate organized gels. The Ca-polygalacturonate complex exhibits a lower energy compared to that of Na-polygalacturonate. The ratio of the Na+ and Ca2+ diffusion coefficients agree well with experimental reports.
Asunto(s)
Calcio/metabolismo , Pectinas/química , Pectinas/metabolismo , Sodio/metabolismo , Sitios de Unión , Conformación de Carbohidratos , Transporte Iónico , Modelos Moleculares , Plantas/metabolismo , TermodinámicaRESUMEN
The interaction between beta-cyclodextrin and five mono- and disubstituted benzenes in water was investigated by means of molecular dynamics. The trajectories were calculated for each system, imposing a 1:1 host-guest stoichiometry with 512 water molecules. Periodic boundary conditions were adopted. The results account for the formation of stable adducts and the predicted geometry agrees with experimental circular dichroism data.
Asunto(s)
Benceno/química , Simulación por Computador , Ciclodextrinas/química , beta-Ciclodextrinas , Compuestos de Anilina/química , Catecoles/química , Modelos Moleculares , Nitrofenoles/química , Fenol/químicaRESUMEN
S. E. M. study of the dorsal anterior one third of male Schistosoma bovis and of the anterior ventral border of the gynaecophoric duct. S. bovis was previously described as possessing spineless tubercles. This is so in specimens obtained from experimentally infected rodents, but in cattle, on the contrary, when conditions are favourable, teguments have spiny tubercles. Two morphological types have been observed: the first in Bos taurus from Sardinia, the second in domestic (Bos indicus) and wild (Hippotragus equinus and Damaliscus korrigum) bovids from Senegal, Tchad and Centrafrican Republic.