RESUMEN
Alzheimer's disease (AD) is a neurodegenerative disorder caused by the deposition of the amyloid-beta peptide (Aß) in senile plaques and cerebral vasculature. Its neurotoxic mechanisms are associated with the generation of oxidative stress and reactive astrogliosis that cause neuronal death and memory impairment. Estrogens reduce the rate of Azheimer's disease because of their antioxidant activity. Prolame (N-(3-hydroxy-1,3,5(10)-estratrien-17ß-yl)-3-hydroxypropylamine) is an aminoestrogen with estrogenic and antithrombotic effects. In our study we evaluated the role of prolame on Aß(25-35)-caused oxidative stress, reactive astrogliosis, and impairment of spatial memory(.) The Aß(25-35) (100 µM/µl) or vehicle was injected into the CA1 subfield of the hippocampus of the rat. The subcutaneous injection of prolame (400 µl, 50 nM) or sesame oil (400 µl) started 1 day before the Aß(25-35) injection and was continued for another 29 days. The results showed a significant impairment of spatial memory evident 30 days after the Aß(25-35) injection. The prolame treatment significantly reduced spatial-memory impairment and decreased lipid peroxidation, reactive oxygen species, and reactive gliosis. It also restored the eNOS and nNOS expression to normal levels. In conclusion the aminoestrogen prolame should be considered as an alternative in the treatment of Alzheimer's disease.
Asunto(s)
Estrenos/farmacología , Discapacidades para el Aprendizaje/tratamiento farmacológico , Trastornos de la Memoria/tratamiento farmacológico , Fármacos Neuroprotectores/farmacología , Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Alzheimer/fisiopatología , Péptidos beta-Amiloides/toxicidad , Animales , Modelos Animales de Enfermedad , Estrenos/administración & dosificación , Hipocampo/efectos de los fármacos , Hipocampo/fisiopatología , Discapacidades para el Aprendizaje/fisiopatología , Peroxidación de Lípido/efectos de los fármacos , Masculino , Trastornos de la Memoria/fisiopatología , Fármacos Neuroprotectores/administración & dosificación , Óxido Nítrico Sintasa de Tipo I/metabolismo , Óxido Nítrico Sintasa de Tipo III/metabolismo , Estrés Oxidativo/efectos de los fármacos , Fragmentos de Péptidos/toxicidad , Ratas , Ratas Wistar , Especies Reactivas de Oxígeno/metabolismoRESUMEN
In addition to causing overt nociception, intraplantar (ipl) endothelin (ET)-1 injection into the rat hind paw induces hyperalgesia to mechanical stimuli, mediated via local ET(B) receptors coupled to protein kinase (PK) C, but not PKA. The present study further examines the intracellular signaling mechanisms underlying this effect of ET-1. ET-1 (30 pmol) or phospate-buffered saline (PBS) was injected ipl in rats and the threshold of responsiveness to mechanical stimulation was assessed repeatedly each hour up to 8 hrs and 24 hrs, using the dynamic plantar aesthesiometer test, which detects the minimal pressure required to evoke paw withdrawal. Different groups were treated, 15 mins before ET-1 administration, with ipsilateral injection of selective inhibitors of either phospholipase (PL) A2 (1 nmol PACOCF3), PLC (30 pmol U73122), PKC (1 nmol GF109203X), p38 mitogen-activated protein kinase (MAPK; 30 nmol SB203580), extracellular signal-regulated kinase (ERK1/2; 30 nmol PD98059), c-Jun N-terminal kinase (JNK; 30 nmol SP600125), or vehicle, to assess their influence on the hyperalgesic response. The mechanical hyperalgesia caused by ET-1 started 2 hrs after injection, peaked at 5 hrs (PBS, 29 +/- 0.5 g; ET-1, 17 +/- 1.3 g) and lasted up to 8 hrs. The inhibitors of PLC, PKC, p38 MAPK, ERK1/2, and JNK caused long-lasting reductions of the mechanical hyperalgesia (inhibitions at 4 hrs of 100%, 90%, 97%, 90%, and 100%, respectively), but the PLA2 inhibitor reduced hyperalgesia only at 4 hrs (by 58%). Thus, mechanical hyperalgesia triggered by ET-1 in the rat hind paw depends importantly on signaling pathways involving PLC, PKC, p38 MAPK, ERK1/2, and JNK, whereas the contribution of PLA2 is relatively minor.
Asunto(s)
Endotelina-1/farmacología , Hiperalgesia/inducido químicamente , Proteína Quinasa C/metabolismo , Fosfolipasas de Tipo C/metabolismo , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismo , Animales , Inhibidores Enzimáticos/farmacología , Estrenos/administración & dosificación , Estrenos/farmacología , Imidazoles/administración & dosificación , Imidazoles/farmacología , Indoles/administración & dosificación , Indoles/farmacología , Inyecciones Intradérmicas , Masculino , Maleimidas/administración & dosificación , Maleimidas/farmacología , Proteína Quinasa C/antagonistas & inhibidores , Piridinas/administración & dosificación , Piridinas/farmacología , Pirrolidinonas/administración & dosificación , Pirrolidinonas/farmacología , Ratas , Ratas Wistar , Tiempo de Reacción , Transducción de Señal/efectos de los fármacos , Fosfolipasas de Tipo C/antagonistas & inhibidores , Proteínas Quinasas p38 Activadas por Mitógenos/antagonistas & inhibidoresRESUMEN
Estrogens have been associated with thromboembolic events. Our group has described the anticoagulant effect of 17 beta-aminoestrogens in rodents, potentially new alternative estrogenic agents without thrombogenic risk. This work compares the contrasting effects of estradiol and the 17 beta-aminoestrogens (prolame, butolame, and pentolame) on blood clotting time. Ovariectomized CD1 mice received a single injection of 17beta-aminoestrogens, estradiol (20 to 80 mg/kg), or vehicle. Estradiol decreased blood clotting time from -10% to -25% (48 h; P<0.01) and 17 beta-aminoestrogens increased it, differing in latency (approximately 12 h; +48%, P<0.01) and duration (approximately 72 h +58%, P<0.01). In male Wistar rats, similar effects (pentolame +45%; estradiol -31%; P<0.01) were observed 48 h after five consecutive daily injections of 1000 microg/animal/day. The maximum procoagulant effect of estradiol was obtained after 72 h with 10 microg/animal/day (-45%; P<0.01). 17 Beta-aminoestrogens always produced opposite effects to those of estradiol on blood coagulation.
Asunto(s)
Coagulación Sanguínea/efectos de los fármacos , Congéneres del Estradiol/farmacología , Estradiol/farmacología , Amino Alcoholes/farmacología , Animales , Relación Dosis-Respuesta a Droga , Estradiol/administración & dosificación , Congéneres del Estradiol/administración & dosificación , Estrenos/administración & dosificación , Estrenos/farmacología , Femenino , Masculino , Ratones , Ovariectomía , Ratas , Ratas WistarRESUMEN
Administration of exogenous estrogens has been associated with an increase of thromboembolic events. The 17 beta-aminoestrogens produce anticoagulant effects contrasting with the procoagulant effects of the natural occurring estradiol in rodents. This work compares the estrogenic effects induced by 17 beta-aminoestrogens prolame, butolame, pentolame, and estradiol in vivo models. Dose-response curves were performed using immature CD1 mice and Wistar rats. The animals were injected with estradiol or 17 beta-aminoestrogens (0.01 to 1000 microg/kg), or vehicle. The uterine wet and dry weights were determined. The 17 beta-aminoestrogens increased uterine weight in a dose-dependent manner. The uterotrophic effect produced by estradiol induced lower ED50 (6.5 and 4 microg/kg) and higher E(max) values (+523-350%) in mice as compared with those from the rat, indicating more susceptibility of the mice model. The 17 beta-aminoestrogens are partial estrogenic agonists with a relative uterotrophic effect of estradiol (100%) from 9-86%. Only the ED50 values of 17 beta-aminoestrogens in CD1 mice showed a direct correlation to the length of the amine group substitution in C-17 since their efficacy and potency were in the order: prolame>butolame>pentolame.
Asunto(s)
Congéneres del Estradiol/farmacología , Útero/efectos de los fármacos , Amino Alcoholes/administración & dosificación , Amino Alcoholes/farmacología , Animales , Relación Dosis-Respuesta a Droga , Estradiol/administración & dosificación , Estradiol/farmacología , Congéneres del Estradiol/administración & dosificación , Estrenos/administración & dosificación , Estrenos/farmacología , Femenino , Ratones , Tamaño de los Órganos/efectos de los fármacos , Ratas , Ratas Wistar , Útero/anatomía & histologíaRESUMEN
To compare the efficacy and safety of two protocols using a combination of aglepristone and cloprostenol for the treatment of open cervix pyometra in the bitch and to describe the progesterone (P4) serum profiles before and during treatments, 15 bitches were randomly allocated into two treatment groups: I (n = 8): aglepristone was administered at 10mg/kg, s.c., on Days 1, 3, 8, and 15 (if not cured), combined with cloprostenol at the dose of 1 microg/kg, s.c., on Days 3 and 8, and II (n = 7): received the same treatment with aglepristone as Treatment I but cloprostenol on Days 3, 5, 8 10, 12, and 15 (if not cured). Before the beginning of the treatments and then on Days 8, 15, and 29 all bitches were evaluated for clinical signs, side effects, hemogram, serum P4 concentrations, and uterus diameters. Bitches in both treatment groups, with (n = 6) or without (n = 9; > or =1.2 ng/ml) initial basal P4 serum concentrations, achieved treatment success without side effects and no significant differences, either on Day 15 (6/8 for Treatment I and 4/7 for Treatment II) or on Day 29 (2/8 for Treatment I and 3/7 for Treatment II). In both treatments groups, clinical signs, blood parameters, and uterine diameters improved to normal values throughout the experiments. A significant interaction between day and treatment was found for percentage change in P4 when all bitches were considered together. Redevelopment of pyometra in the next estrous cycle occurred in 20% of the bitches. One nonrecurrent bitch was mated and whelped a normal litter. It is concluded that these two combined protocols proved to be efficient and safe in reversing clinical signs of open cervix pyometra independently of initial P4 concentrations and that the number of cloprostenol administrations seemed to have an effect on P4 serum changes throughout treatments.
Asunto(s)
Cloprostenol/administración & dosificación , Enfermedades de los Perros/tratamiento farmacológico , Estrenos/administración & dosificación , Útero/patología , Excreción Vaginal/veterinaria , Combinación Amoxicilina-Clavulanato de Potasio/administración & dosificación , Animales , Cuello del Útero/patología , Perros , Quimioterapia Combinada , Hiperplasia Endometrial/tratamiento farmacológico , Hiperplasia Endometrial/veterinaria , Ciclo Estral , Femenino , Progesterona/sangre , Supuración , Ultrasonografía , Útero/diagnóstico por imagen , Excreción Vaginal/patologíaRESUMEN
The synthetic androgen 7alpha-methyl-19-nortestosterone (MENT) is a potent suppressor of gonadotrophin that has several advantages for long term administration to normal or hypoandrogenic men. The aim of this study was to examine MENT serum concentrations following subdermal insertion of MENT acetate (MENT Ac) implants and their effects on gonadotrophins, testosterone, dihydrotestosterone (DHT), sex hormone-binding globulin, prostate specific antigen and insulin-like growth factor-1 serum concentrations in normal men. A total of 45 healthy men were recruited at three clinics. Each subject received one, two or four implants for 28 days. Serum samples were obtained before insertion and on days 8, 15, 22, 29, 36 and 43 after implant insertion. The average daily dose delivered in vivo by one implant was approximately 500 microg. One, two or four MENT Ac implants produced dose dependent and sustained serum MENT concentrations for the entire duration of treatment of 0.7 +/- 0.1, 1.2 +/- 0.1 and 2.0 +/- 0.1 nmol/l respectively. This treatment induced a dose dependent decrease in gonadotrophin and androgen serum levels. Two and four implants induced maximal suppression that was maintained throughout treatment and was completely reversed after removal of the implants. The mean decreases were 93 +/- 1% for testosterone, 80 +/- 3% for DHT, 97 +/- 1% for luteinizing hormone and 95 +/- 1% for follicle stimulating hormone. No serious adverse reactions were reported by the volunteers and no consistent changes in clinical chemistry and haematology were found. These results indicate that MENT Ac implants are an efficient way of MENT administration and confirm the potent gonadotrophin and androgen suppressive effect of this drug.