Efectos del tratamiento antioxidante en la activación del eje hipotálamo-hipófiso-adrenal inducida por el consumo de dietas ricas en sacarosa / Effects of antioxidant treatment on the activation of the hipotalamo-hipofiso-adrenal axis induced by the consumption of sucrose rich diets

Introducción: dados los efectos pleiotrópicos de los glucocorticoides (GCs) sobre el metabolismo, los niveles excesivos y sostenidos de GCs circulantes tienen efectos deletéreos e incrementan la morbilidad y mortalidad cardiovascular. Objetivos: estudiar el efecto de la terapia antioxidante (con ácido lipoico o melatonina) sobre la hiperactivación del eje hipotálamo-hipófiso-adrenal (HHA) en animales alimentados con dieta rica en sacarosa (DRS). Materiales y métodos: se evaluó la actividad del eje HHA y se determinaron parámetros hormonales, de estrés oxidativo y de inflamación en la adenohipófisis de animales tratados con DRS durante tres semanas. Resultados: los animales del grupo DRS mostraron mayores niveles circulantes de hormona adrenocorticotropa (ACTH, por sus siglas en inglés) y corticosterona. En paralelo se detectó un aumento en la expresión del polipéptido precursor (proopiomelanocortina, POMC) y de ACTH en la adenohipófisis, donde también se observó un aumento de lipoperóxidos y proteínas nitradas en tirosina (daño oxidativo), un mayor número de macrófagos tisulares y un incremento en la producción de IL-1beta. El tratamiento antioxidante previno los cambios en estos parámetros. En particular la melatonina también normalizó la actividad del eje HHA y la expresión hipofisaria de POMC. Conclusiones: la sobrecarga metabólica inducida por la administración de DRS genera daño oxidativo e inflamación en la adenohipófisis. La activación de los macrófagos tisulares producida en consecuencia podría impactar sobre los corticotropos hipofisarios e inducir su hiperfunción. La melatonina podría utilizarse como herramienta terapéutica para normalizar la actividad del eje HHA en modelos de obesidad por dieta.

Introduction: given the pleiotropic effects of glucocorticoids (GCs) on metabolism, excessive and sustained levels of circulating GCs, have deleterious effects and increase cardiovascular morbidity and mortality. Objectives: to study the effect of antioxidant therapy on hyperactivation of the hypothalamic-pituitary-adrenal (HPA) axis in animals fed a sucrose-rich diet (SRD). Materials and methods: the activity of the HPA axis was evaluated and hormonal, oxidative stress and inflammation parameters were determined in the adenohypophysis of animals treated with SRD for trhee weeks. Results: animals from the SRD group showed higher circulating levels of adrenocorticotropic hormone (ACTH) and corticosterone. In parallel, an increase in the expression of the polypeptide precursors, POMC and ACTH were detected in the adenohypophysis. We also observed an increase in lipoperoxides and proteins nitrated in tyrosine (oxidative damage), a greater number of tissue macrophages and an increase in the production of IL-1beta. Antioxidant treatment prevented all these changes. In particular, melatonin also normalized the activity of the HPA axis and pituitary expression of POMC. Conclusions: the metabolic overload induced by the administration of SRD generates oxidative damage and inflammation in the adenohypophysis. Activation of tissue macrophages could affect, in turn, pituitary corticotrophs inducing their activation. Melatonin could be used as a therapeutic tool to normalize the activity of the HPA axis in diet obesity models.

Melatonin prevents early pituitary dysfunction induced by sucrose-rich diets.

While physiological levels of glucocorticoids are required to ensure proper functions of the body, consistently high levels may engender several deleterious consequences. We have previously shown an increase in the activity of the hypothalamic-pituitary-adrenal (HPA) axis in rats fed sucrose-rich diets (SRD). The main goal of this study was to analyze the processes involved in the modulation of the pituitary production of ACTH by SRD, and to test melatonin as a possible therapeutic agent for the prevention of the HPA axis dysfunction. Male Wistar rats were fed standard chow and either SRD (30% sucrose in the drinking water) or plain water for three weeks. Melatonin was administered as subcutaneous pellets. Results showed that SRD treatment induced an increase in systemic ACTH and corticosterone levels and a decrease in melatonin levels. In the pituitary gland, we also detected an increase in the expression levels of proopiomelanocortin (POMC) that was accompanied by increased levels of: lipoperoxides, nitro-tyrosine modified proteins, catalase, heme oxygenase-1, interleukin-1ß mRNA, and by an increase in the tissue number of inflammatory cells (F4/80 and Iba-1 positive cells). Melatonin treatment prevented all these systemic and pituitary changes as well as the increase in POMC expression induced by incubation of AtT-20 corticotrophs with conditioned media obtained from stimulated macrophages. In conclusion, stimulation of POMC/ACTH production in rats fed a SRD could involve the generation of oxidative stress and inflammation in the pituitary gland. Melatonin treatment prevented these effects and normalized the activity of the HPA axis.

Maternal administration of melatonin exerts short- and long-term neuroprotective effects on the offspring from lipopolysaccharide-treated mice.

Preterm birth is a major contributor to early and delayed physical and cognitive impairment. Epidemiological and experimental data indicate that maternal infections are a significant and preventable cause of preterm birth. Recently, melatonin has been suggested to exert neuroprotective effects in several models of brain injury. Here, we sought to investigate whether the administration of melatonin is able to prevent lipopolysaccharide (LPS)-induced fetal brain damage in a model of LPS-induced preterm labor. For this purpose, 15-day pregnant BALB/c mice received intraperitoneally 2 doses of LPS or vehicle: the first one at 10:00 hours (0.26 mg/kg) and the second at 13:00 hours (0.52 mg/kg). On day 14 of pregnancy, a group of mice was subcutaneously implanted with a pellet of 25 mg melatonin. This experimental protocol resulted in 100% of preterm birth and pup death in the LPS group and a 50% of term birth and pup survival in the melatonin + LPS group. In the absence of melatonin, fetuses from LPS-treated mothers showed histological signs of brain damage, microglial/macrophage activation, and higher levels of IL-1ß, inducible nitric oxide synthase (NOS), and neuronal NOS mRNAs as well as increased histone acetyltransferase activity and histone H3 hyperacetylation. In contrast, antenatal administration of melatonin prevented LPS-induced fetal brain damage. Moreover, when behavioral traits were analyzed in the offspring from control, melatonin, and melatonin + LPS, no significant differences were found, suggesting that melatonin prevented LPS-induced long-term neurodevelopmental impairments. Collectively, our results suggest that melatonin could be a new therapeutic tool to prevent fetal brain damage and its long-term consequences induced by maternal inflammation.

Therapeutic effect of melatonin in experimental uveitis.

Uveitis is a common ophthalmic disorder that can be induced in hamsters by a single intravitreal injection of bacterial lipopolysaccharide (LPS). To examine the therapeutic effects of melatonin on uveitis, a pellet of melatonin was implanted subcutaneously 2 hours before the intravitreal injection of either vehicle or LPS. Both 24 hours and 8 days after the injection, inflammatory responses were evaluated in terms of i) the integrity of the blood-ocular barrier, ii) clinical signs, iii) histopathological studies, and iv) retinal function. Melatonin reduced the leakage of proteins and cells in the anterior segment of LPS-injected eyes, decreased clinical signs such as dilation of the iris and conjunctival vessels, and flare in the anterior chamber, and protected the ultrastructure of the blood-ocular barrier. A remarkable disorganization of rod outer segment membranous disks was observed in animals injected with LPS, whereas no morphological changes in photoreceptor outer segments were observed in animals treated with melatonin. Furthermore, melatonin prevented a decrease in LPS-induced electroretinographic activity. In addition, melatonin significantly abrogated the LPS-induced increase in retinal nitric-oxide synthase activity, tumor necrosis factor-alpha, and nuclear factor kappaB p50 and p65 subunit levels. These results indicate that melatonin prevents the clinical, biochemical, histological, ultrastructural, and functional consequences of experimental uveitis, likely through a nuclear factor kappaB-dependent mechanism, and support the use of melatonin as a new therapeutic strategy for the treatment of uveitis.