Papel de la glía en la enfermedad de Alzheimer. Futuras implicaciones terapéuticas / The role of glial cells in Alzheimer disease: potential therapeutic implications

Introducción: La enfermedad de Alzheimer (EA) es una compleja enfermedad neurodegenerativa caracterizada por inflamación, neurotoxicidad, estrés oxidativo y gliosis reactiva. La microglía y los astrocitos no solo actúan como células presentadoras de antígenos, sino que constituyen células efectoras, liberando moléculas proinflamatorias que promueven la excitotoxicidad y la neurodegeneración. Objetivo: En la presente revisión bibliográfica se discute el papel de la glía, específicamente de la microglía y el astrocito en la fisiopatología de la EA y las posibles implicaciones terapéuticas. Desarrollo: La emergente evidencia del papel patogénico y la activación de vías de inflamación a partir de la microglía y el astrocito, los factores neurotóxicos liberados por estas células cuando están activadas, y cómo estos pueden desestabilizar la homeostasis del sistema nervioso central, sostienen la idea de que la inflamación inducida por la glía amplifica la EA. Conclusiones: La inhibición de la inflamación por inactivación de la glía, pudiera reducir la producción de factores que contribuyen con la toxicidad, resultando ser un beneficio clínico. La microglía y el astrocito constituyen blancos terapéuticos en el desarrollo de nuevos fármacos para combatir esta enfermedad. Estrategias terapéuticas diseñadas para contrarrestar el efecto perjudicial de la sobreactivación de estas poblaciones celulares deben ser investigadas

Introduction: Alzheimer (AD) disease is a complex neurodegenerative disease characterised by inflammation, neurotoxicity, oxidative stress, and reactive gliosis. Microglia and astrocytes not only act as antigen-presenting cells, but also function as effector cells releasing pro-inflammatory molecules that promote excitotoxicity and neurodegeneration Objective: In the present review we discuss the role of glia, specifically microglia and astrocytes, in the pathophysiology of AD and possible therapeutic implications. Development: The growing body of evidence suggesting that microglia and astrocytes play a pathogenic role and activate inflammation pathways, the neurotoxic factors released by these cells when activated, and the way these factors may disrupt the homeostasis of the central nervous system all support the hypothesis that glia-induced inflammation exacerbates AD. Conclusions: Inhibiting inflammation by deactivating glial cells may reduce the production of factors which contribute to neurotoxicity, and therefore result in clinical improvement. Microglia and astrocytes are therapeutic targets for the development of new drugs to combat this disease. Therapeutic strategies designed to counter the detrimental effects of overactivation of these cell populations should be investigated

The role of glial cells in Alzheimer disease: potential therapeutic implications.

INTRODUCTION: Alzheimer (AD) disease is a complex neurodegenerative disease characterised by inflammation, neurotoxicity, oxidative stress, and reactive gliosis. Microglia and astrocytes not only act as antigen-presenting cells, but also function as effector cells releasing pro-inflammatory molecules that promote excitotoxicity and neurodegeneration. OBJECTIVE: In the present review we discuss the role of glia, specifically microglia and astrocytes, in the pathophysiology of AD and possible therapeutic implications. DEVELOPMENT: The growing body of evidence suggesting that microglia and astrocytes play a pathogenic role and activate inflammation pathways, the neurotoxic factors released by these cells when activated, and the way these factors may disrupt the homeostasis of the central nervous system all support the hypothesis that glia-induced inflammation exacerbates AD. CONCLUSIONS: Inhibiting inflammation by deactivating glial cells may reduce the production of factors which contribute to neurotoxicity, and therefore result in clinical improvement. Microglia and astrocytes are therapeutic targets for the development of new drugs to combat this disease. Therapeutic strategies designed to counter the detrimental effects of overactivation of these cell populations should be investigated.

Respuesta inmune en la neuromielitis óptica / Immune response in optic neuromyelitis

La neuromielitis óptica es una enfermedad inflamatoria, desmielinizante y autoinmune del sistema nervioso central. En el presente trabajo se realiza una revisión de los diferentes mecanismos involucrados en la patogénesis de la neuromielitis óptica, se analiza el papel de los eosinófilos, de los anticuerpos contra antígenos propios y de las células T reguladoras en la enfermedad. En la neuromielitis óptica existe un predominio de la respuesta inmune humoral, la enfermedad se caracteriza por el depósito de inmunocomplejos, activación del complemento, producción de anticuerpos contra proteínas de la mielina y reclutamiento de eosinófilos en las lesiones. Existe además un aumento de la expresión de receptores de quimiocinas como el CCR3, específico de células TH2, la enfermedad está asociada predominantemente a una respuesta TH2(AU)

The Optic Neuromyelitis is an inflammatory and autoimmune illness of the central nervous system. Presently work is carried out a revision of the different mechanisms involved in the pathogenesis of the Optic Neuromyelitis, the paper of the eosinophils is analyzed, of the antibodies against own antigens and of the regulatory T cells in the illness. In the Optic Neuromyelitis is very important the humoral response, the illness exists it is characterized by the immunocomplex deposit, activation of the complement, production of antibodies against proteins of the myelin and eosinophils recruitment in the lesions. It also exists an increase of the expression of chemokines receptors like the CCR3, specific of TH2 cells; the illness is associate predominantly to a TH2 response(AU)

Respuesta inmune en la neuromielitis óptica / Immune response in optic neuromyelitis

La neuromielitis óptica es una enfermedad inflamatoria, desmielinizante y autoinmune del sistema nervioso central. En el presente trabajo se realiza una revisión de los diferentes mecanismos involucrados en la patogénesis de la neuromielitis óptica, se analiza el papel de los eosinófilos, de los anticuerpos contra antígenos propios y de las células T reguladoras en la enfermedad. En la neuromielitis óptica existe un predominio de la respuesta inmune humoral, la enfermedad se caracteriza por el depósito de inmuno complejos, activación del complemento, producción de anticuerpos contra proteínas de la mielina y reclutamiento de eosinófilos en las lesiones. Existe además un aumento de la expresión de receptores de quimiocinas como el CCR3, específico de células TH2, la enfermedad está asociada predominantemente a una respuesta TH2

The Optic Neuromyelitis is an inflammatory and autoimmune illness of the central nervous system. Presently work is carried out a revision of the different mechanisms involved in the pathogenesis of the Optic Neuromyelitis, the paper of the eosinophils is analyzed, of the antibodies against own antigens and of the regulatory T cells in the illness. In the Optic Neuromyelitis is very important the humoral response, the illnes sexists it is characterized by the immunocomplex deposit, activation of the complement, production of antibodies against proteins of the myelin and eosinophils recruitment in the lesions. It also exists an increase of the expression of chemokines receptors like the CCR3, specific of TH2 cells; the illness is associate predominantly to a TH2 response

Neuromielitis óptica: principales diferencias con la esclerosis múltiple / Optic neuromyelitis: main differences with multiple sclerosis

La neuromielitis optica o síndrome de Devic es una enfermedad inflamatoria, desmielinizante y autoinmune del sistema nervioso central. Se caracteriza por ataques de neuritis óptica y mielitis, pudiendo producir ceguera, gran invalidez neurológica e incluso la muerte a corto plazo. Hasta el momento no existe un tratamiento efectivo, la terapia se centra en el tratamiento de los ataques agudos, la prevención médica de las complicaciones y la rehabilitación. Se realiza una revisión de esta enfermedad poco común, considerando que su prevalencia en nuestro país ha ido en aumento y se establece una comparación entre la neuromielitis óptica y la esclerosis múltiple, basándose en las principales características clínico-epidemiológicas, que distinguen estas dos patologías, consideradas por muchos variantes clínicas de una misma enfermedad(AU)

The optic neuromyelitis or syndrome of Devic is an inflammatory and autoimmune illness of the central nervous system. It is characterized by attacks of optic neuritis and myelitis, being able to produce blindness, great neurological disability and even the short term death. Until the moment an effective treatment doesn't exist, the therapy is centred in the treatment of the acute attacks, the medical prevention of the complications and the rehabilitation. This article is a revision of this not very common illness, considering that its prevalence in our country has gone in increase. We compare between the optic neuromyelitis and the multiple sclerosis, being based on the main ones characteristic clinical-epidemic that distinguishes these two pathologies, considered by many clinical variants of oneself illness(AU)

Neuromielitis óptica. Principales diferencias con la esclerosis múltiple / Optic neuromyelitis. Main differences with multiple sclerosis

La neuromielitis optica o síndrome de Devic es una enfermedad inflamatoria, desmielinizante y autoinmune del sistema nervioso central. Se caracteriza por ataques de neuritis óptica y mielitis, pudiendo producir ceguera, gran invalidez neurológica e incluso la muerte a corto plazo. Hasta el momento no existe un tratamiento efectivo, la terapia se centra en el tratamiento de los ataques agudos, la prevención médica de las complicaciones y la rehabilitación. Se realiza una revisión de esta enfermedad poco común, considerando que su prevalencia en nuestro país ha ido en aumento y se establece una comparación entre la neuromiel itisóptica y la esclerosis múltiple, basándose en las principales características clínico-epidemiológicas, que distinguen estas dos patologías, consideradas por muchos variantes clínicas de una misma enfermedad

The optic neuromyelitis or syndrome of Devic is an inflammatory and autoimmune illness of the central nervous system. It is characterized by attacks of optic neuritis and myelitis, being able to produce blindness, great neurological disability and even the short term death. Until the moment an effective treatment doesn't exist, the therapy is centred in the treatment of the acute attacks, the medical prevention of the complications and the rehabilitation. This article is a revision of this not very common illness, considering that its prevalence in our country has gone in increase. We compare between the optic neuromyelitis and the multiple sclerosis, being based on the main ones characteristic clinical-epidemic that distinguishes these two pathologies, considered by many clinical variants of oneself illness

[Optic neuromyelitis. Main differences with multiple sclerosis]. / Neuromielitis óptica. Principales diferencias con la esclerosis múltiple.

The optic neuromyelitis or syndrome of Devic is an inflammatory and autoimmune illness of the central nervous system. It is characterized by attacks of optic neuritis and myelitis, being able to produce blindness, great neurological disability and even the short term death. Until the moment an effective treatment doesn't exist, the therapy is centred in the treatment of the acute attacks, the medical prevention of the complications and the rehabilitation. This article is a revision of this not very common illness, considering that its prevalence in our country has gone in increase. We compare between the optic neuromyelitis and the multiple sclerosis, being based on the main ones characteristic clinical-epidemic that distinguishes these two pathologies, considered by many clinical variants of oneself illness.

[Immune response in optic neuromyelitis]. / Respuesta inmune en la neuromielitis óptica.

The Optic Neuromyelitis is an inflammatory and autoimmune illness of the central nervous system. Presently work is carried out a revision of the different mechanisms involved in the pathogenesis of the Optic Neuromyelitis, the paper of the eosinophils is analyzed, of the antibodies against own antigens and of the regulatory T cells in the illness. In the Optic Neuromyelitis is very important the humoral response, the illness exists it is characterized by the immunocomplex deposit, activation of the complement, production of antibodies against proteins of the myelin and eosinophils recruitment in the lesions. It also exists an increase of the expression of chemokines receptors like the CCR3, specific of TH2 cells; the illness is associate predominantly to a TH2 response.

Effect of parasitism on the pharmacokinetic disposition of ivermectin in lambs.

The aim of this study was to investigate the effect of parasitism on plasma availability and pharmacokinetic behaviour of ivermectin (IVM) in lambs. Fourteen greyface Suffolk lambs (26.8 +/- 2.2 kg body weight) were selected for this study. Seven pairs of lambs were allocated into two groups in order to obtain an approximately even distribution. Group I (non-parasitized) was pre-treated by three repeated administrations of 5 mg/kg of fenbendazole (Panacur), in order to maintain a parasite-free condition. The lambs in group II (parasitized) did not receive any anthelmintic treatment and the natural infection was sustained by an oral inoculation of infective stages of nematode parasites. After the 85-day pre-treatment period both groups of animals were treated with IVM (200 microg/kg, Ivomec) by subcutaneous injection in the shoulder area. Both groups of animals were maintained under similar conditions of feeding and management. Blood samples were collected by jugular puncture at different times between 0.5 h and 25 days post-treatment. After plasma extraction and derivatization, samples were analysed by high-performance liquid chromatography with fluorescence detection. A computerized kinetic analysis was performed and data were compared using the unpaired Student's t-test. The parent molecule was detected in plasma between 30 min and either 12 (parasitized) or 20 (no parasitized) days post-IVM treatment. The area under the curve values of the parasitized group (75.2 +/- 15.5 ng x d/ml) were significantly lower that those observed in the parasite-free group (134.3 +/- 15.7 ng x d/ml). The mean residence time (MRT) of the parasitized group (2.93 +/- 0.16 days) was significantly lower than the MRT of healthy group (3.93 +/- 0.29 days). The results of this study have shown that a change in body condition followed by a parasitic infection is associated with significant changes in plasma disposition of IVM when it is administered subcutaneously to parasitized lambs. Therefore, variations in the condition induced by parasitism should be considered when these anthelmintics are used for treating parasitized animals.

Plasma profiles of ivermectin in horses following oral or intramuscular administration.

A study was undertaken in order to evaluate and compare ivermectin's (IVM) plasma disposition kinetic parameters after oral or intramuscular (IM) administration in horses. Ten clinically healthy adult horses, weighing 380-496 kg body weight (BW), were allocated to two experimental groups of five horses. Group I, was treated with an oral paste formulation of IVM at the manufacturer's recommended dose of 0.2 mg/kg BW. Group II, was treated IM with an injectable 1% formulation of IVM at a dose of 0.2 mg/kg BW. Blood samples were collected by jugular puncture at different times between 0.5 h and 75 days post-treatment. After plasma extraction and derivatization, samples were analysed by high-performance liquid chromatography with fluorescence detection. A computerized kinetic analysis was performed, and data were compared using the Wilcoxon signed rank test. The parent molecule was detected in plasma between 30 min and either 20 (oral) or 40 (IM) days post-treatment. Significant differences were found for the time corresponding to peak plasma concentrations (tmax) and for absorption half-life. Peak plasma concentrations (Cmax) of 51.3 +/- 16.1 ng/ml (mean +/- SD) were obtained after oral administration and of 31.4 +/- 6.0 ng/ml for the IM route. The values for area under concentration-time curve were 137.1 +/- 35.9 ng day/ml for the group treated orally, and 303.2 +/- 4.3 ng day/ml for the IM treated group. The mean plasma residence times were 4.2 +/- 0.4 and 8.9 +/- 0.7 days for oral and IM-treated groups, respectively. The results of this study show that the route of administration considerably affects the disposition of IVM. A significant difference in bioavailabilty and half-life of elimination of IVM was observed after IM administration compared with oral administration. A close relationship between pharmacokinetic profiles and the clinical efficacy of IVM was established.

Pharmacokinetics of doramectin and ivermectin after oral administration in horses.

A study was undertaken in order to compare plasma disposition kinetic parameters of doramectin (DRM) and ivermectin (IVM) in horses after oral administration. Ten crossbreed adult horses, clinically healthy, weighing 380-470 kg body weight (bw) were selected for study. Faecal examinations were performed to determine faecal parasite egg counts. Horses were allocated to two groups of five animals to provide an even distribution considering the variables sex, body weight and faecal egg count. Group I, were treated with an oral paste formulation of IVM at 0.2 mg/kg b/w and Group II, were treated with an oral dose of 0.2 mg/kg bw of DRM prepared as paste from the injectable formulation for oral administration. Blood samples were collected by jugular puncture between 0 h and 75 days post-treatment. Plasma was separated and later solid phase extraction and derivatization samples were analysed by high performance liquid chromatography (HPLC); a computerised kinetic analysis was carried out. Data were compared using the Mann-Whitney U-test. The mean plasma concentrations of DRM and IVM after oral administration in horses were detected until 30 and 20 days, respectively. Both drugs showed similar patterns of absorption and no significant differences were found for peak concentration, the time to peak concentration, or for absorptive half-life. The terminal elimination half-life was significantly (P<0.05) longer in the DRM treated group than for the IVM treated group. The differences observed in the elimination half-life explain the longer mean residence time and high values of area under the concentration time curve for the group treated with DRM, which are 30% higher than those of the IVM group. Considering its pharmacokinetics, tolerance and anthelmintic efficacy, the oral administration of DRM, could be an alternative to IVM for the control of parasitic diseases of horses.

Faecal excretion profile of moxidectin and ivermectin after oral administration in horses.

A study was undertaken to evaluate and compare faecal excretion of moxidectin and ivermectin in horses after oral administration of commercially available preparations. Ten clinically healthy adult horses, weighing 390-446 kg body weight (b.w.), were allocated to two experimental groups. Group I was treated with an oral gel formulation of moxidectin at the manufacturer's recommended therapeutic dose of 0.4 mg/kg b.w. Group II was treated with an oral paste formulation of ivermectin at the recommended dose of 0.2 mg/kg b.w. Faecal samples were collected at different times between 1 and 75 days post-treatment. After faecal drug extraction and derivatization, samples were analysed by High Performance Liquid Chromatography using fluorescence detection and computerized kinetic analysis. For both drugs the maximum concentration level was reached at 2.5 days post administration. The ivermectin treatment groups' faecal concentrations remained above the detectable level for 40 days (0.6 +/- 0.3 ng/g), whereas the moxidectin treatment group remained above the detectable level for 75 days (4.3 +/- 2.8 ng/g). Ivermectin presented a faster elimination rate than moxidectin, reaching 90% of the total drug excreted in faeces at four days post-treatment, whereas moxidectin reached similar levels at eight days post-treatment. No significant differences were observed for the values of maximum faecal concentration (C(max)) and time of C(max)(T(max)) between both groups of horses, demonstrating similar patterns of drug transference from plasma to the gastrointestinal tract. The values of the area under the faecal concentration time curve were slightly higher in the moxidectin treatment group (7104 +/- 2277 ng.day/g) but were not significantly different from those obtained in the ivermectin treatment group (5642 +/- 1122 ng.day/g). The results demonstrate that although a 100% higher dose level of moxidectin was used, attaining higher plasma concentration levels and more prolonged excretion and gut secretion than ivermectin, the concentration in faeces only represented 44.3+/- 18.0% of the total parental drug administered compared to 74.3 +/- 20.2% for ivermectin. This suggests a higher level of metabolization for moxidectin in the horse.

Comparison of the pharmacokinetics of moxidectin (Equest) and ivermectin (Eqvalan) in horses.

A study was undertaken in order to evaluate and compare plasma disposition kinetic parameters of moxidectin and ivermectin after oral administration of their commercially available preparations in horses. Ten clinically healthy adult horses, weighing 390-446 kg body weight (b.w.), were allocated to two experimental groups of five horses. Group I was treated with an oral gel formulation of moxidectin (MXD) at the manufacturers recommended therapeutic dose of 0.4 mg/kg bw. Group II was treated with an oral paste formulation of ivermectin (IVM) at the manufacturers recommended dose of 0.2 mg/kg b.w. Blood samples were collected by jugular puncture at different times between 0.5 h and 75 days post-treatment. After plasma extraction and derivatization, samples were analysed by HPLC with fluorescence detection. Computerized kinetic analysis was carried out. The parent molecules were detected in plasma between 30 min and either 30 (IVM) or 75 (MXD) days post-treatment. Both drugs showed similar patterns of absorption and no significant difference was found for the time corresponding to peak plasma concentrations or for absorption half-life. Peak plasma concentrations (Cmax) of 70.3+/-10.7 ng/mL (mean +/- SD) were obtained for MXD and 44.0+/-23.1 ng/mL for IVM. Moreover, the values for area under concentration-time curve (AUC) were 363.6+/-66.0 ng x d/mL for the MXD treated group, and 132.7+/-47.3 ng x d/mL for the IVM treated group. The mean plasma residence times (MRT) were 18.4+/-4.4 and 4.8+/-0.6 days for MXD and IVM treated groups, respectively. The results showed a more prolonged residence of MXD in horses as demonstrated by a four-fold longer MRT than for IVM. The longer residence and the higher concentrations found for MXD in comparison to IVM could possibly explain a more prolonged anthelmintic effect. It is concluded that in horses the commercial preparation of MXD presents a pharmacokinetic profile which differs significantly from that found for a commercial preparation of IVM. To some extent these results likely reflect differences in formulation and doses.