RESUMEN
The primary visual cortex (V1) is the first step in visual information processing and its function may be modulated by acetylcholine through nicotinic receptors (nAChRs). Since our previous work demonstrated that visual acuity and cortical spatial resolution limit were significantly reduced in α7 knock-out (KO) mice in the absence of retinal alterations, we decided to characterize the contribution of homomeric α7 nicotinic receptors (α7nAChRs) to visual information processing at the cortical level. We evaluated long-term forms of synaptic plasticity in occipital slices containing V1 from α7 KO mice and in wild-type (WT) slices perfused with nAChRs selective blocking agents. In α7 KO mice slices, electrophysiological recordings demonstrated the absence of long-term potentiation (LTP) and long-term depression (LTD) in layer II/III after the stimulation of different intracortical pathways (layer IV or II/III). Furthermore, the acute and selective blockade of α7nAChRs in slices from WT mice with either α-bungarotoxin or methyllycaconitine did not alter the expression of LTP and LTD. Conversely, the perfusion with the unspecific nAChRs antagonist mecamylamine impaired LTP and LTD. Our results suggest the presence of impaired synaptic plasticity in the V1 of α7 KO mice and indicate a different contribution of nAChRs to visual cortex function.
Asunto(s)
Plasticidad Neuronal/fisiología , Antagonistas Nicotínicos/farmacología , Sinapsis/efectos de los fármacos , Corteza Visual/fisiología , Receptor Nicotínico de Acetilcolina alfa 7/metabolismo , Animales , Bungarotoxinas/farmacología , Hipocampo/efectos de los fármacos , Hipocampo/metabolismo , Potenciación a Largo Plazo/fisiología , Mecamilamina/farmacología , Ratones , Ratones Noqueados , Agonistas Nicotínicos/farmacología , Corteza Visual/efectos de los fármacos , Receptor Nicotínico de Acetilcolina alfa 7/deficienciaRESUMEN
Although amyotrophic lateral sclerosis (ALS) has long been considered as a lower motor neuron (MN) disease, degeneration of upper MNs arising from a combination of mechanisms including insufficient growth factor signaling and enhanced extracellular glutamate levels is now well documented. The observation that these mechanisms are altered in presymptomatic superoxide dismutase (SOD1) mice, an ALS mouse model, suggests that defective primary motor cortex (M1) synaptic activity might precede the onset of motor disturbances. To examine this point, we assessed the composition of AMPAR and NMDAR subunits and of the alphaCa²(+)/calmodulin-dependent kinase autophosphorylation at threonine-286 in the triton insoluble fraction from the M1 in postnatal P80-P85 SOD1(G93A) and wild-type mice. We show that presymptomatic SOD1(G93A) exhibit a selective decrease of NR2A subunit expression and of the alphaCa²(+)/calmodulin-dependent kinase autophosphorylation at threonine-286 in the triton insoluble fraction of upper MNs synapses. These molecular alterations are associated with synaptic plasticity defects, and a reduction in upper MN dendritic outgrowth revealing that abnormal neuronal connectivity in the M1 region precedes the onset of motor symptoms. We suggest that the progressive disruption of M1 corticocortical connections resulting from the SOD1(G93A) mutation might extend to adjacent regions and promote development of cognitive/dementia alterations frequently associated with ALS.
Asunto(s)
Esclerosis Amiotrófica Lateral/fisiopatología , Proteína Quinasa Tipo 2 Dependiente de Calcio Calmodulina/metabolismo , Neuronas Motoras/metabolismo , Plasticidad Neuronal/fisiología , Receptores de N-Metil-D-Aspartato/biosíntesis , Esclerosis Amiotrófica Lateral/metabolismo , Esclerosis Amiotrófica Lateral/patología , Animales , Western Blotting , Modelos Animales de Enfermedad , Potenciales Evocados , Técnica del Anticuerpo Fluorescente , Humanos , Ratones , Ratones Transgénicos , Microscopía Confocal , Neuronas Motoras/patología , Mutación , Fosforilación , Superóxido Dismutasa/genética , Superóxido Dismutasa-1 , Treonina/metabolismoRESUMEN
BACKGROUND: Visuo-spatial disturbances could represent a clinical feature of early stage Alzheimer's disease (AD). The magnocellular (M) pathway has anatomo-physiological characteristic which make it more suitable for detecting form, motion and depth compared with parvocellular one (P). OBJECTIVE: Aim of our study was to evaluate specific visual subsystem involvement in a group of AD patients, recording isoluminant chromatic and luminance pattern electroretinograms and pattern visual evoked potentials. MATERIAL AND METHODS: data were obtained from 15 AD patients (9 females and 6 males, mean age+/-1SD: 77.6+/-4.01 years) not yet undergoing any treatment, and from 10 age-matched healthy controls. Diagnosis of probable AD was clinically and neuroradiologically established. PERGs were recorded monocularly in response to equiluminant red-green (R-G), blue-yellow (B-Y) and luminance yellow-black (Y-Bk) horizontal square gratings of 0.3c/deg and 90% contrast, reversed at 1Hz. VEPs were recorded in response to full-field (14 deg) equiluminant chromatic R-G, B-Y and luminance Y-Bk sinusoidal gratings of 2c/deg, presented in onset (300ms)-offset (700ms) mode, at the contrast levels of 90%. RESULTS: All data were retrieved in terms of peak-amplitude and latency and assessed using the Student's t-test for paired data. Temporal differences of PERGs and VEPs, evoked by Y-Bk grating in AD patients compared with controls, suggest a specific impairment of the magnocellular stream. CONCLUSIONS: Our study support the hypothesis that the impairment of the PERGs and VEPs arising from the magnocellular streams of visual processing may indicate a primary dysfunction of the M-pathways in AD.
Asunto(s)
Enfermedad de Alzheimer/fisiopatología , Electrorretinografía/métodos , Potenciales Evocados Visuales/fisiología , Cuerpos Geniculados/fisiopatología , Vías Visuales/fisiopatología , Percepción Visual , Anciano , Anciano de 80 o más Años , Animales , Femenino , Humanos , Masculino , Estimulación LuminosaRESUMEN
Sucralfate is a drug used in the treatment of gastric and duodenal ulcer; it is cytoprotective and able to increase the bioavailability of several growth factors, modulating the wound healing process. In this study we tested the possible therapeutic effect of Sucralfate in the treatment of ulcerative lesions occurring in uterine cervix; to investigate such effect we used an experimental rat model of cervicitis in which the uPAR and EGFR expression were evaluated. Cervicitis was induced in wild and ovariectomized Wistar female rats by an acetic acid-soaked tampon. The animals were divided into two main groups (4 and 7 days) and Sucralfate was administered topically until the day they were sacrificed. In order to distinguish physiological and drug-induced healing, quantitative and qualitative uPAR and EGFR expression were evaluated by using Western blot and Immunohistochemistry techniques. Western blot analysis demonstrated an increased expression of both receptors after 4 days from wounding in wild and ovariectomized animals. In particular in ovariectomized animals the expression of uPAR and EGFR increased after 4 days while it reduced following the administration of Sucralfate. In wild rats the same was observed for uPAR expression, while EGFR was different; in fact, its expression increased significantly at day 4 in the animals treated with the drug and only at day 7 in those untreated. Immunohistochemistry highlighted a noteworthy epithelial colocalization of EGFR and uPAR after 4 days in the animals treated with Sucralfate. We conclude that Sucralfate can promote the healing of ulcerative cervicitis and moreover, it reduces the normal healing time because of its modulatory property on uPAR and EGFR expression.
Asunto(s)
Antiulcerosos/uso terapéutico , Receptores ErbB/análisis , Receptores de Superficie Celular/análisis , Sucralfato/uso terapéutico , Cervicitis Uterina/tratamiento farmacológico , Animales , Modelos Animales de Enfermedad , Femenino , Inmunohistoquímica , Ovariectomía , Ratas , Ratas Wistar , Receptores del Activador de Plasminógeno Tipo Uroquinasa , Sucralfato/farmacología , Cervicitis Uterina/metabolismoAsunto(s)
Acetilcolina/metabolismo , Plasticidad Neuronal/fisiología , Receptores Muscarínicos/metabolismo , Corteza Visual/fisiología , Animales , Ganglios Basales/citología , Ganglios Basales/fisiología , Humanos , Neuronas/citología , Neuronas/fisiología , Transmisión Sináptica/fisiología , Corteza Visual/anatomía & histologíaRESUMEN
In this study, we investigated the effect of 1,25(OH)2D3 on proteinuria and on the alteration of slit diaphragm-associated proteins induced by anti-Thy 1.1 in Wistar rats. Four groups of animals were studied: group I, anti-Thy 1.1 treated rats; group II, anti-Thy1.1 treated group that at day 2, after the onset of overt proteinuria, started the treatment with 1,25(OH)2D3; group III, normal control rats injected with vehicle alone; group IV, rats that received only 1,25(OH)2D3. At day 2, in group I and II, before the administration of 1,25(OH)2D3, protein excretion was significantly increased when compared to controls. Overt proteinuria was maintained until day 14 in group I whereas in group II protein excretion was significantly reduced from day 3 to day 14. Moreover, treatment with 1,25(OH)2D3 abrogated podocytes injury, detected as desmin expression and loss of nephrin and zonula occludens-1 (ZO-1), two slit diaphragm-associated proteins, and glomerular polyanion staining, that were observed in group I. In conclusion, these results suggest that 1,25(OH)2D3 administrated with a therapeutic regiment may revert proteinuria, counteracting glomerular podocyte injury.
Asunto(s)
Calcitriol/uso terapéutico , Glomerulonefritis Membranoproliferativa/tratamiento farmacológico , Glomerulonefritis Membranoproliferativa/metabolismo , Glomérulos Renales/efectos de los fármacos , Glomérulos Renales/metabolismo , Vitaminas/uso terapéutico , Animales , Desmina/biosíntesis , Femenino , Técnica del Anticuerpo Fluorescente , Glomerulonefritis Membranoproliferativa/patología , Glomérulos Renales/patología , Proteínas de la Membrana/biosíntesis , Fosfoproteínas/biosíntesis , Polielectrolitos , Polímeros/metabolismo , Proteinuria/metabolismo , Ratas , Ratas Wistar , Fijación del Tejido , Proteína de la Zonula Occludens-1RESUMEN
The objective of this study was to assess whether tyrosol and caffeic acid are able to inhibit lipopolysaccharide (LPS)-induced tumor necrosis factor (TNF)-alpha release. TNF is one of the most important cytokines involved in inflammatory reactions. The results show that both tyrosol and caffeic acid are able to inhibit LPS-induced TNF-alpha release from human monocytes, even at low doses. Their mechanisms of action are discussed and we conclude that high doses of the two compounds are not required to achieve effective inhibition of inflammatory reactions due to TNF-alpha release.
Asunto(s)
Ácidos Cafeicos/farmacología , Lipopolisacáridos/farmacología , Monocitos/efectos de los fármacos , Monocitos/metabolismo , Alcohol Feniletílico/análogos & derivados , Alcohol Feniletílico/farmacología , Factor de Necrosis Tumoral alfa/antagonistas & inhibidores , Ácidos Cafeicos/administración & dosificación , Células Cultivadas , Relación Dosis-Respuesta a Droga , Sinergismo Farmacológico , Humanos , Alcohol Feniletílico/administración & dosificación , VinoRESUMEN
Some well-known antioxidant phenols present in extravirgin olive oil have also been found in white wine. Both tyrosol and caffeic acid are phenols that are present not only in extravirgin olive oil, but also in wine, especially white wine. Their antioxidant properties are well known, but their biological effects have not yet been elucidated. In a previous study we found that these substances were able to inhibit tumor necrosis factor alpha release. The present study was carried out to assess whether these compounds are able to inhibit other inflammatory cytokines, such as interleukin-1 beta and interleukin-6. The results show that low concentrations of these phenols, which can be found in the bloodstream after intake of moderate quantities of white wine, exert significant inhibitory activity on the release of several inflammatory cytokines.