Influence of hormonal status on enkephalin-degrading aminopeptidase activity in the HPA axis of female mice.

Opioids are involved in the regulation of hypothalamus-pituitary-adrenal (HPA) axis activity under physiological conditions. In the present work, we analyzed the influence of ovariectomy and estradiol (E), progesterone (P) or estradiol plus progesterone (E+P) replacement on soluble (S) and membrane-bound (MB) enkephalin-degrading aminopeptidase activity (EDA) in the HPA axis. Female mice (Balb/C) were distributed in 15 groups of 10 animals each: sham-operated controls (C), ovariectomized controls (OV-C), and ovariectomized mice treated with increasing doses of E (10, 20 or 40 mg/kg), P (100, 200 or 400 mg/kg) or E+P (10+100, 20+200 or 40+400 mg/kg). In hypothalamus, ovariectomy increased both S and MB EDA activities, whereas E replacement returned them to control levels, although MB EDA activity increased again after the replacement with 40 mg/kg E. P replacement increased S EDA activity, but returned MB EDA activity to control levels. The replacement of E+P returned both S and MB EDA activities to control levels, although MB EDA activity was lower than control values after the replacement with 10+100 mg/kg E+P. In pituitary, neither ovariectomy nor the replacement of E or E+P changed S EDA, although the highest concentrations of P increased S EDA activity. However, ovariectomy increased MB EDA and E replacement returned the activity to control or below control levels, depending on the concentration used. However, P administration returned the activity to control or below control levels depending on the concentration used, although 200 mg/kg P had no effects on MB EDA. E+P replacement returned pituitary MB EDA activity to control levels. In adrenal glands, ovariectomy did change either S or MB EDA. However, E, P or E+P replacement decreased S EDA activity in different degrees, depending of the dose administrated. No changes were detected in MB EDA after hormone replacement. These results indicate that female steroid hormones influence EDA activity at different levels of HPA axis.

Effects of orchidectomy and testosterone replacement on mouse pyrrolidone carboxypeptidase activity in the HPA axis.

Pyrrolidone carboxypeptidase, also known as pyroglutamyl aminopeptidase, removes pyroglutamyl terminal residues from biologically active peptides such as thyrotropin-releasing hormone. The aim of the present work was to study the influence of orchidectomy and testosterone replacement on soluble (pyrrolidone carboxypeptidase type I) and membrane-bound (pyrrolidone carboxypeptidase type II) activities in the hypothalamus-pituitary-adrenal axis. Forty male mice (Balb/C) were distributed into five groups: sham-operated controls, orchidectomized, and orchidectomized treated with increasing doses of testosterone in each group (3, 6 and 12 mg/kg). In the hypothalamus, orchidectomy increased pyrrolidone carboxypeptidase type I, whereas the highest dose of testosterone returned this activity to control levels. In the pituitary, neither pyrrolidone carboxypeptidase type I nor type II activities changed after orchidectomy, although both activities increased after administration of testosterone in both cases. On the other hand, orchidectomy increased pyrrolidone carboxypeptidase type I and type II activities in adrenal glands, while testosterone replacement returned it to control levels. These results suggest that testosterone differentially modulates pyrrolidone carboxypeptidase type I and type II activities, and therefore also their endogenous substrate regulation. Thus, the influence of sex hormones in the physiology of the HPA axis through the modulation of the Pyrrolidone carboxypeptidase type I and type II activities is of great importance on stress and neuropathology associated with HPA dysfunction

Actividad de las aminopeptidasas séricas en un modelo animal de cáncer de mama inducido por N-metil-nitrosourea / Activity of serum aminopeptidases in an animal model of N-metil-nitrosourea- induced breast cancer

Los factores hormonales responsables de la proliferación del tejido mamario normal durante la pubertad y los cambios cíclicos del ciclo menstrual podrían estar implicados en la promoción, la progresión y la aparición del cáncer de mama en humanos. Se ha sugerido que las enzimas proteolíticas del tipo de las aminopeptidasas, cuyo papel fisiológico consiste en la regulación de diversos péptidos biológicamente activos, podrían participar en el desarrollo del cáncer de mama. La finalidad del presente trabajo es analizar la actividad de un amplio espectro de aminopeptidasas en el suero de ratas con tumores de mama inducidos por N-metil-nitrosourea (NMU), para evaluar su posible valor como marcadores biológicos de esta enfermedad. La inducción de tumores con NMU mostró una incidencia tumoral del 60 por ciento, con un período de latencia medio de 113 días y un número medio de tumores por rata de 1,93. Las actividades específicas de aminopeptidasa N (APN) aminopeptidasa B (APB) aminopeptidasa A (APA) (aspartato aminopeptidasa [AspAP] y glutamato aminopeptidasa [AspAP], oxitocinasa y pirrolidón carboxipeptidasa se analizaron fluorimétricamente utilizando como sustrato las correspondientes aminoacil-naftilamidas. Los animales con cáncer de mama inducido por NMU mostraron incrementos significativos en los valores séricos de APB (32 por ciento; p < 0,01), GluAP (54 por ciento; p < 0,05) y oxitocinasa (45 por ciento; p < 0,05), mientras que los valores de pirrolidón carboxipeptidasa estaban disminuidos (28 por ciento; p < 0,05). Estos cambios pueden reflejar alteraciones en el metabolismo de las angiotensinas, la oxitocina y la hormona liberadora de gonadotropinas, que pueden ser, al menos en parte, responsables del inicio y/o desarrollo de la enfermedad (AU)

Effects of orchidectomy and testosterone replacement on mouse enkephalin-degrading aminopeptidase activity in the HPA axis.

Opiates are involved in the regulation of several functions in the hypothalamus-pituitary-adrenal (HPA) axis under physiological conditions. The aim of the present work is to study the influence of orchidectomy and testosterone (T) replacement on soluble (S) and membrane bound (MB) enkephalin-degrading aminopeptidase (EDA) activities in the HPA axis. Forty male mice (Balb/C) were distributed in five groups: sham-operated control (C), orchidectomized (OR-C), and orchidectomized treated with increasing doses of T (3, 6 or 12 mg/kg). In hypothalamus, orchidectomy did not modify either S or MB EDA, although T replacement increased S but not MB EDA. In pituitary, neither S nor MB EDA activities changed with orchidectomy, although both activities changed after T replacement. On the other hand, in adrenal glands, orchidectomy increased S and MB EDA activities, whereas T replacement returned both activities to control levels. These results suggest a direct effect of T in S and MB EDA activities and therefore, an influence on their endogenous substrates regulation.

[Physiology of the neuropeptides]. / Fisiología de los neuropéptidos.

In the present review, the characteristics of mammalian neuropeptides have been studied. Neuropeptides are widely distributed not only in the nervous system but also in the periphery. They are synthesised by neurons as large precursor molecules (pre propeptides) which have to be cleaved and modified in order to form the mature neuropeptides. Neuropeptides may exert actions as neurotransmitters, neuromodulators and/or neurohormones. In the neurons, they coexist with classic transmitters and often with other peptides. After their releasing, they bind to especific receptors to exert their action in the target cell. Most of these receptors belongs to a family of G protein coupled receptors. Finally, peptidases are the enzymes involved in the degradation of neuropeptides. Conclusions. In the last years, the number of known neuropeptides and the understanding of their functions have been increased. With these data, present investigations are looking for the treatment of different pathologies associated with alterations in the physiology of neuropeptides.

Fisiología de los neuropéptidos / Physiology of neuropeptides

Objetivos. En la presente revisión se pretenden analizar las características generales de los neuropéptidos de los mamíferos.Desarrollo. Los neuropéptidos son sustancias distribuidas de forma ubicua tanto en el sistema nervioso como en la periferia. Se sintetizan en la neurona a partir de prepropéptidos de gran tamaño que se escinden y se modifican hasta formar el neuropéptido maduro. Los neuropéptidos pueden ejercer funciones como neurotransmisores, pero también se han descrito como neuromoduladores o neurohormonas. En la neurona se almacenan en vesículas donde coexisten con neurotransmisores clásicos y, a veces, con otros péptidos. Una vez liberados, se unirán a receptores específicos para ejercer su acción en la célula diana. La mayoría de estos receptores pertenecen a la familia de receptores acoplados a una proteína G. Finalmente, las peptidasas son las enzimas encargadas de su degradación. Conclusiones. En los últimos años, el número de neuropéptidos se ha incrementado considerablemente y además son cada vez mejor conocidas las funciones en las que se ven implicados. En base a estos datos, las investigaciones recientes se están dirigiendo hacia la búsqueda de tratamientos para patologías asociadas con alteraciones de los neuropéptidos (AU)