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Introducción. En nuestro modelo experimental, la infección aguda por Trypanosoma cruzi (T. cruzi) en ratas adultas cursa con una parasitemia poco evidente, mientras que en los animales prepúberes (PP) se registran parasitemias más elevadas. Estas discrepancias podrían asociarse a la inmadurez inmunológica que exhiben los animales más jóvenes, pero asimismo, a la diferente madurez sexual del huésped al momento de la infección. Siendo la testosterona (T) una hormona capaz de influir sobre las células del sistema inmune y en consecuencia modificar el curso de las infecciones parasitarias, nos propusimos evaluar el efecto de dosis fisiológicas de T sobre la miocarditis aguda en fase temprana en ratas PP. Material y métodos. Se inocularon 1 millón de T. cruzi al destete y dos dosis de T de 1 mg/kg de peso, previo al T. cruzi. Se realizaron los controles respectivos, incluido un grupo experimental que recibió bicalutamida, antagonista de la T (5 mg/kg/día) +T+T. cruzi. Se evaluó parasitemia a los 7, 10 y 14 días post infección (pi) y se realizó el estudio anátomo-patológico de corazón, timo y bazo a los 4, 7 y 14 días pi. Resultados. A los 14 días pi, los animales que recibieron dosis fisiológicas de T presentaron un incremento significativo en la parasitemia y desarrollaron una mayor esplenomegalia que el resto de los grupos infectados. El estudio histológico de esos grupos reveló una miocarditis de intensidad similar -moderada a intensa- y nidos de amastigotes, mientras que en los animales sacrificados al día 4 y 7, se observó nidos de amastigotes sin reacción inflamatoria. Los controles no presentaron alteraciones histológicas. Conclusiones. La administración de T en los animales PP, previo a la infección con T. cruzi, propició la replicación temprana del parásito, evidenciada por el aumento en la parasitemia; sin embargo, no fue capaz de modificar la lesión cardíaca aguda en fase temprana ni tardía.

Background. According to our experimental model, along the acute phase of Chagas illness, adult rats infected with Trypanosome cruzi (T. cruzi) presents very low and almost undetectable parasitemias, whereas in prepubertal animals (PP) parasitemias reported were higher than in the adult ones. These differences could be associated with the immunological immaturity exhibited by younger animals, but also owing to the different sexual maturity of the host at the time of infection. As testosterone (T) is a hormone that can influence immune system cells and thus modify the course of parasitic infections, we have evaluated the effect of physiological doses of T on early acute stage of myocarditis in rats PP. Methods and material. Two doses of T (1 mg/kg) were inoculated to weaning rats (prior infection) followed by the inoculation of 1 million of T. cruzi trypomastigotes. The proper controls were performed, including an experimental group which received a concomitant therapy of bicalutamide, an antagonist of T (5 mg/kg/day), plus T and T. cruzi inoculation. Parasitemia was assessed at 7, 10 and 14 days post infection (pi) and the anatomopathological studies of heart, thymus and spleen were also performed at 4, 7 and 14 days pi. Results. At 14 day pi, those animals receiving physiological doses of T showed a significant increase in parasitemia and developed a higher splenomegaly compare to the rest of the infected groups. The histological examination of these groups presented a myocarditis of similar intensity -moderate to intense-, and amastigotes nests, while at days 4 and 7, amastigotes nests were observed without inflammatory reaction. Controls did not present histological alterations. Conclusions. Administration of T in the PP animals prior to T. cruzi infection led to an early parasite replication, as evidenced by the increase in parasitemia, however, it was not able to modify the acute cardiac injury during the early or late stage.

Introdução. Em nosso modelo experimental, a infecção aguda pelo Trypanosoma cruzi (T. cruzi) em ratos adultos cursos com parasitemia evidente pouco, enquanto que em animais pré-púberes (PP) são registrados parasitemias mais elevadas. Estas discrepâncias podem estar associadas à imaturidade imunológica exibidos por animais mais jovens, mas também para a diferente maturidade sexual do parasitado no momento da infecção. Como o hormônio testosterona (T) que pode influenciar as células do sistema imunológico e, assim, modificar o curso das infecções parasitárias, nós avaliamos o efeito de doses fisiológicas de T em estágio inicial miocardite aguda em ratos PP. Material e métodos. Um milhão de T. cruzi foram inoculados a desmame e duas doses de T de 1 mg / kg, antes a T. cruzi. Respectivos controles foram realizados, incluindo um grupo experimental que receberam bicalutamida, um antagonista da T (5 mg/kg/dia) + T + T. cruzi. Parasitemia foi avaliada aos 7, 10 e 14 dias após a infecção (ai) e realizado o estudo patológico do coração, timo e baço a 4, 7 e 14 dias ai. Resultados. Aos 14 dias ai, os animais que receberam doses fisiológicas de T mostraram um aumento significativo na parasitemia e desenvolveram uma maior esplenomegalia que outros grupos infectados. Exame histológico desses grupos revelou uma intensidade similar de miocardite -moderada a intensa-, e ninhos de amastigotas, enquanto em animais sacrificados nos dias 4 e 7, ninhos de amastigotas foram observados sem reação inflamatória. Os controles não apresentaram alterações histológicas. Conclusões. A administração de T nos animais PP antes da infecção com T. cruzi, levou à replicação inicial do parasita, como evidenciado pelo aumento da parasitemia, entretanto, não foi capaz de modificar a lesão cardíaca aguda na fase precoce ou tardia.

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Chagas' disease is a major tropical disease for which a cure for chronic phase does not exist yet. Trypanosoma cruzi trans-sialidase (TS) seems to be involved in relevant processes such as infectivity, host survival and, very importantly, disease pathogenesis. In this study, we show that mice vaccinated with an engineered enzymatically deficient mutant TS containing the catalytic domain without the immunodominant SAPA (Shed Acute Phase Antigen) repeats, were highly protected against T. cruzi infection. Adult male BALB/c mice were immunized with mutant protein, purified from Pichia pastoris yeast, using three inoculations in Freund's adjuvant. All immunized mice were protected against challenge with a lethal dose of T. cruzi trypomastigotes. The protected immunized mice developed no clinical or tissue evidence of infection throughout the study. In contrast, 60-90% mortality and 100% occurrence of myocardial lesions were observed in the non-immunized counterparts. Titers of circulating antibody against TS did not correlate with protection, while anti-SAPA antibodies were coincident with disease severity. Further studies indicated that a single inoculation of mutant recombinant protein in Freund's complete adjuvant was not associated with blood or organic alterations, per se. Mutant TS vaccination seems to be a promising tool for immune intervention strategies in Chagas' disease, aimed at preventing T. cruzi-related heart tissue damage.

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Progress in the control and treatment of pain may be facilitated by a better understanding of mechanisms underlying nociceptive processing. Cannabinoids and opioids are endogenous modulator of pain sensation, but therapies based in these compounds are not completely exploited because of their side effects. To test the role of cannabinoid receptor type 1 (CB1-R) inhibition in nociception, we performed a subchronic administration of the CB1-R antagonist N-(piperidin-1-yl)-5-(4-iodophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide (AM281) in mice. This treatment provoked analgesia in peripheral thermal and visceral models of pain. Analysis of genes encoded for the opioid system in the spinal cord showed an increase in the expression of genes encoded for the κ-opioid system in AM281-injected mice compared with vehicle-injected ones. Furthermore, systemic administration of nor-binaltorphimine, a κ-opioid receptor antagonist, blocked AM281-induced analgesia. Finally, c-fos expression in the dorsal spinal cord and higher centers of pain processing after noxious stimulation were significantly lower in AM281-injected mice than in vehicle-injected animals, indicating that dynorphin could block nociceptive information transmission at the spinal cord level. These results indicate the existence of a cross-talk between opioid and cannabinoid systems in nociception. Furthermore, the results suggest that CB1-R antagonists could be useful as a new therapeutic approach for pain relief.

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Progress in the control and treatment of pain may be facilitated by a better understanding of mechanisms underlying nociceptive processing. Here we show that mice subjected to an intermittent fasting diet (IFD) display markedly reduced responses in models of thermal and visceral pain compared with mice fed ad libitum (AL). Pharmacological analyses suggest that a change in the endogenous kappa-opioid system underlies IFD-induced analgesia. The levels of prodynorphin mRNA and kappa-opioid receptors in the spinal cord are higher in IFD than in AL mice. Furthermore, in spinal cord nuclear protein extracts, the activity of the transcriptional repressor DREAM (downstream regulatory element antagonist modulator), the main regulator of prodynorphin expression, is lower in IFD than in AL mice. Finally, c-Fos expression in dorsal spinal cord after noxious stimulation is significantly lower in IFD than in AL animals, indicating that dynorphin could block nociceptive information at the spinal cord. These results suggest that dietary restriction together with administration of kappa-opioid agonists could be useful as a new therapeutic approach for pain relief.

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