Upregulation of Nrf2 attenuates Angiostrongylus cantonensis-induced parasitic meningitis in mice.

Abstract

Background: Angiostrongylus cantonensis is a food-borne parasite that can infect mammals, including humans, causing angiostrongyliasis. The nuclear factor E2-related factor 2 (Nrf2) is a transcription factor that plays a crucial role in the host's antioxidant defense and inflammation mechanisms. Herein, this study investigates the anti-inflammatory effects of Nrf2 in A. cantonensis-induced parasitic meningitis in mice.

Methods: We used animal infection and treatment, larvae collection, western blotting, enzyme-linked immunosorbent assay (ELISA), hematoxylin and eosin (H&E) stain, blood-brain barrier (BBB) permeability assays, and an NAD(P)H quinone dehydrogenase 1 (NQO1) enzyme activity, reactive oxygen species (ROS), and superoxide dismutase (SOD) assay kit in this study.

Results: Our findings revealed that larvae recovery, BBB permeability, and inflammatory mediators (interleukin (IL)-1β, IL-6, IL-17A, and tumor necrosis factor (TNF)-α) were increased in A. cantonensis-infected mice. However, p-Nrf2 levels were slightly increased in infected groups. To better understand the modulatory role of Nrf2 in the parasitic meningitis, we also treated A. cantonensis-infected mice with oltipraz (an Nrf2 activator) and trigonelline (an Nrf2 inhibitor). The larvae recovery, BBB permeability, and levels of inflammatory mediators were significantly decreased in the albendazole alone, oltipraz, and albendazole-oltipraz co-treatment groups, particularly in albendazole-oltipraz co-treatment groups. In contrast, trigonelline treatment resulted in increased levels of larvae recovery, BBB permeability, and inflammatory mediators. Moreover, since Nrf2 is involved in the regulation of antioxidant enzymes, we also examined the expression of ROS, NQO1, and SOD. ROS levels were significantly increased in infected groups but decreased in the albendazole alone, oltipraz alone, and albendazole-oltipraz co-treatment groups. NQO1 and SOD levels were significantly decreased in infected groups, but these levels were notably restored during treatment with albendazole alone, oltipraz alone, and albendazole-oltipraz co-treatment.

Conclusions: Our findings revealed the albendazole-Nrf2 activator co-treatment effectively suppressed excessive inflammation compared with the anthelmintics drug (albendazole) treatment alone, and Nrf2 activation might produce a synergistic effect in the inflammatory response of the brain in mice with angiostrongyliasis.