Abstract
In the late phase of Trypanosoma cruzi infection, parasite persistence and an exaggerated immune response accompanied by oxidative stress play a crucial role in the genesis of Chronic Chagasic Cardiomyopathy (CCC). Current treatments (Benznidazole (BNZ) and Nifurtimox) can effect only the elimination of the parasite, but are ineffective for late stage treatment and for preventing heart damage and disease progression. In vivo trypanocidal and cardioprotective activity has been reported for Lippia alba essential oils (EOs), ascribed to their two major terpenes, limonene and caryophyllene oxide. To investigate the role of antioxidant and immunomodulatory mechanisms behind these properties, chronic-T. cruzi-infected rats were treated with oral synergistic mixtures of the aforementioned EOs. For this purpose, the EOs were optimized through limonene-enrichment fractioning and by the addition of exogenous caryophyllene oxide (LIMOX) and used alone or in combined therapy with subtherapeutic doses of BNZ (LIMOXBNZ). Clinical, toxicity, inflammatory, oxidative, and parasitological (qPCR) parameters were assessed in cardiac tissue. These therapies demonstrated meaningful antioxidant and immunomodulatory activity on markers involved in CCC pathogenesis (IFN-γ, TNF-α, IL-4, IL-10, and iNOS), which could explain their significant trypanocidal properties and their noteworthy role in preventing, and even reversing, the progression of cardiac damage in chronic Chagas disease.
Highlights
Chagas disease is a parasitosis caused by Trypanosoma cruzi that affects approximately10 million people worldwide, of whom around 30% will eventually develop organomegaly of the digestive tract or heart [1]
essential oils (EOs) obtained by the steam distillation technique from fresh and mature carvone-chemotype L. alba leaves were fractionated under reduced pressure for enrichment in the bioactive terpene limonene
This research contributes to clarifying, in a chronic Chagas heart disease (CHD) model in Wistar rats, immunomodulation as a possible trypanocidal and cardioprotective mechanism of LIMOX, a therapy based on a synergistic mixture composed of caryophyllene oxide and a limoneneenriched fraction derived from L. alba EO
Summary
Chagas disease is a parasitosis caused by Trypanosoma cruzi that affects approximately10 million people worldwide, of whom around 30% will eventually develop organomegaly of the digestive tract or heart [1]. Because of the silent course of this parasitosis and the late appearance of its symptoms (usually 8–10 years after acquiring the parasite, and without any other pathognomonic signs), CHD can be confused with other etiologies, delaying timely diagnosis [3] These factors combined have contributed to CHD being presently considered a neglected and high-cost disease, with an average cost of care for chronic cases estimated at USD $44,955 per person [4]. Current treatments available for therapeutic intervention against this infection are based on the use of two nitro-heterocyclic compounds: nitrofuran Nifurtimox (NFX) and nitroimidazole Benznidazole (BNZ) These compounds, well-established for more than 50 years as the conventional therapy against T. cruzi infection, have been found to exhibit limited trypanocidal activity (between 50–80% in the acute phase, and 8–20% in the chronic) [6], with high toxicity due to non-selective oxidative damage
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