Antidepressant-like and Beneficial Effects of a Neoponcirin-Beta-Cyclodextrin Inclusion Complex in Mice Exposed to Prolonged Stress.

Neoponcirin causes anxiolytic-like effects in mice when administered intraperitoneally but not orally. Neoponcirin is non-water-soluble and insoluble in solvents, and in medium acid, it isomerizes, reducing its bioavailability. To improve the pharmacological properties of neoponcirin, we formed a neoponcirin complex with beta-cyclodextrin (NEO/ßCD), which was characterized by FT-IR, UV-Vis, and NMR, and their solubility profile. We evaluated the antidepressant-like effects of NEO/ßCD acutely administered to mice orally in the behavioral paradigms, the tail suspension (TST) and the forced swimming (FST) tests. We also analyzed the benefits of repeated oral doses of NEO/ßCD on depression- and anxiety-like behaviors induced in mice by chronic unpredictable mild stress (CUMS), using the FST, hole board, and open field tests. We determined the stressed mice's expression of stress-related inflammatory cytokines (IL-1ß, IL-6, and TNFα) and corticosterone. Results showed that a single or chronic oral administration of NEO/ßCD caused a robust antidepressant-like effect without affecting the ambulatory activity. In mice under CUMS, NEO/ßCD also produced anxiolytic-like effects and avoided increased corticosterone and IL-1ß levels. The effects of the NEO/ßCD complex were robust in both the acute and the stress chronic models, improving brain neurochemistry and recovering immune responses previously affected by prolonged stress.

Sexual Dimorphism of the Neuroimmunoendocrine Response in the Spleen during a Helminth Infection: A New Role for an Old Player?

The interaction of the nervous, immune, and endocrine systems is crucial in maintaining homeostasis in vertebrates, and vital in mammals. The spleen is a key organ that regulates the neuroimmunoendocrine system. The Taenia crassiceps mouse system is an excellent experimental model to study the complex host-parasite relationship, particularly sex-associated susceptibility to infection. The present study aimed to determine the changes in neurotransmitters, cytokines, sex steroids, and sex-steroid receptors in the spleen of cysticercus-infected male and female mice and whole parasite counts. We found that parasite load was higher in females in comparison to male mice. The levels of the neurotransmitter epinephrine were significantly decreased in infected male animals. The expression of IL-2 and IL-4 in the spleen was markedly increased in infected mice; however, the expression of Interleukin (IL)-10 and interferon (IFN)-γ decreased. We also observed sex-associated differences between non-infected and infected mice. Interestingly, the data show that estradiol levels increased in infected males but decreased in females. Our studies provide evidence that infection leads to changes in neuroimmunoendocrine molecules in the spleen, and these changes are dimorphic and impact the establishment, growth, and reproduction of T. crassiceps. Our findings support the critical role of the neuroimmunoendocrine network in determining sex-associated susceptibility to the helminth parasite.

Los efectos conductuales modulados por las citocinas / Behavioural changes modulated by interleukins

The nervous, endocrine, and immune systems maintain permanent and concerted communication through humoral and neural pathways, which involves neurotransmitters like serotonin and noradrenaline; hormones like cortisol, corticosterone release hormone; and a wide range of inflammatory molecules and their corresponding receptors. Variations in the circulatory levels of these soluble mediators modulate several physiological processes and help to mantain homeostasis in the face of stressful stimuli, regardless whether they are physical like systemic bacterial, viral or parasitical infections, as well as tissular injuries or psychological stress, that is secondary to the individual's perception and processing. Chronic activation of neuro-immune-endocrine interactions induces numerical and functional changes in these systems and behavioral disorders. "Sickness behavior" is one the most studied behavioral disorders that is characterized by the presence of anhedonia, fatigue, psychomotor retardation, decreased appetite, altered sleep patterns, and pain-increased sensitivity. Based on the similarities between the behavioral symptoms of "sickness behavior" and major depression, it has been hypothesized that molecules like cytokines and other inflammatory factors could be involved in the pathophysiology of several neuropsychiatric disorders, such as depression, cognitive dysfunction, fatigue, anxiety and personality disorders as well as neurodegenerative diseases such as Parkinson and Alzheimer. The behavioral disorders in major depression can be induced by single or combined administration of proinflammatory cytokines as well as mitogens or infectious agents that induce significant secretion of wide range of inflammatory molecules. Variations in peripheral and central inflammatory mediators significantly affect the levels of neurotransmitters, such as glutamate, dopamine, and serotonin; p38 MAPK and IDO proteins. The latest data on the involvement of cytokines and neurotransmitters in metabolic pathways have provided various targets for pharmaceutical development and have established new treatment approaches for psychiatric disorders. All this advantages about molecular mecanism involved in behavioural changes will result in the short term in a better quality of life for patients.

Los Sistemas Nervioso, Endocrino e Inmunológico mantienen a través de la vía humoral y neuronal una comunicación permanente y concertada que incluye a las hormonas neurotransmisoras, las citocinas y a sus respectivos receptores expresados en las células que conforman estos tres sistemas. La variación de los niveles de estos mediadores solubles induce la regulación de varios procesos fisiológicos y media la respuesta de nuestro organismo ante la presencia de estímulos estresantes, tanto físicos como psicológicos. La activación crónica de la interacción neuroendocrinoinmunológica favorece la aparición de variaciones numéricas y funcionales en los tres sistemas involucrados y genera alteraciones de tipo conductual. Entre las alteraciones conductuales más estudiadas destaca el llamado "sickness behavior", que se caracteriza por la presencia de anedonia, fatiga, enlentecimiento psicomotor, disminución del apetito, alteraciones en el patrón del sueño y un incremento en la sensibilidad al dolor. Las similitudes entre los síntomas conductuales del "sickness behavior" y la depresión mayor han permitido establecer una hipótesis sobre la participación de las citocinas y otros factores inflamatorios en la fisiopatología de algunos trastornos neuropsiquiátricos como la depresión, la disfunción cognitiva, la fatiga, los trastornos de ansiedad, los de la personalidad y las enfermedades neurodegenerativas como las de Parkinson y de Alzheimer. Las alteraciones conductuales presentes en la depresión mayor pueden ser inducidas por la administración individual o conjunta de citocinas proinflamatorias, de mitógenos o por agentes infecciosos que inducen una importante secreción de moléculas inflamatorias. Las variaciones periféricas y centrales de los mediadores inflamatorios influyen significativamente sobre los neurotransmisores como el glutamato, la dopamina, la serotonina, la proteína p38 MAPK y la indolomina-2-3 dioxigenasa (IDO). Es por ello que actualmente las citocinas, los neurotransmisores al igual que las rutas metabólicas en las que participan son el blanco de nuevos tratamientos para algunos padecimientos psiquiátricos, lo que mejorará la calidad de vida para los pacientes.