Melatonin regulates antioxidant defense and inflammatory response by activating Nrf2-dependent mechanisms and inhibiting NFkappaB expression in middle-aged T. cruzi infected rats

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Brazao, Vania ; Colato, Rafaela Pravato ; Santello, Fabricia Helena ; Duarte, Andressa ; Goulart, Amanda ; Sampaio, Pedro Alexandre ; Silva, Carla B. Pacheco ; Tirapelli, Carlos Renato ; Costa, Rafael M. ; Tostes, Rita C. ; do Prado Jr, Jose Clovis

• Document type: Journal article
• Source: Experimental Gerontology; v. 167, p. 9-pg., 2022-07-26.

Abstract

Oxidative stress with higher levels of leptin and inflammatory response are key processes related to pathogenesis of both T. cruzi infection and aging. Nuclear factor erythroid 2-related factor 2 (Nrf2) controls the expression of several genes implicated in the oxidative stress response in many pathological conditions. Melatonin is a pleiotropic hormone with, antioxidant, anti-inflammatory and anti-aging actions. Then, we hypothesized that Nrf2 response is impaired during the acute T. cruzi (9 days) infection and that melatonin rescues Nrf2 responses. Young (5 weeks-old) and middle-aged (18 months-old) male Wistar rats were infected with T. cruzi. Nrf2 translocation and markers of inflammation and oxidative stress were analyzed in blood and spleen. Increased apoptosis levels and oxidative stress indicators were observed in the rat spleen during T. cruzi infection. These responses were accompanied by decreased Nrf2 expression and increased expression of nuclear factor kappa B (NF kappa B). Melatonin (5 mg/kg/day; p.o. gavage) attenuated the superoxide anion (O-2(-center dot)) and hydrogen peroxide (H2O2) production induced by T. cruzi infection. Increased expressions of catalase and superoxide dismutase (SOD) were detected in the spleen of melatonin-treated rats infected with T. cruzi. Melatonin treatment inhibited the spleen NF-kappa B activation and downregulates the levels of circulating interleukin (IL)-4, IL-10 and tumor necrosis factor (TNF)-alpha in T. cruzi middle-aged infected rats. Increased levels of the chemokine CXCL1 in middle-aged control rats was observed, confirming that aging alters the production of this chemokine. In T. cruzi infected young animals, CXCL1 was up-regulated when compared to non-infected young ones. For young or middle-aged animals, melatonin treatment had no significant effect on CXCL1 levels. Our findings demonstrate an important role for Nrf2/NF-kB regulation as a possible mechanism by which melatonin attenuates oxidative stress, and provide new insights for further studies of this indoleamine as a therapeutic co-adjuvant agent against T. cruzi infection. (AU)

• FAPESP's process: 15/09806-3 - Melatonin and senescence : study the modulation of the immune system during experimental infection with Trypanosoma cruzi.
• Grantee: José Clóvis do Prado Júnior
• Support Opportunities: Regular Research Grants