Immunomodulation and Antioxidant Activities as Possible Trypanocidal and Cardioprotective Mechanisms of Major Terpenes from Lippia alba Essential Oils in an Experimental Model of Chronic Chagas Disease

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.

Citral-rich fractions of <i>Lippia alba</i> essential oils as immunoresponsive and anti-<i>Candida albicans</i> additives for collagen membranes in guided bone regeneration

“…The addition of oil fractions to chlorhexidine increased the CC 50 value of the biocide 2-fold, decreasing its necrotizing effects, alterations to mitochondria (disruption of mitochondrial membrane potential and induction of superoxide), and damage to genomic DNA. Comparable results have been reported previously [16,[22][23][24][25][26]: combinations of limonene or citral, or mixtures rich in these terpenes enhanced the pharmacological performance of chemotherapy or antiparasitic drugs in vitro and in vivo while minimizing their cytotoxic effects on normal host cells. The selectivity of these antiproliferative actions was ascribed to a possible bimodal activity of these terpenes, which may act as antioxidants under physiological conditions or switch to pro-oxidant activity in cells with increased susceptibility to oxidative stress (e.g., protozoa, yeast, or cancer cells) [23].…”

“…Comparable results have been reported previously [16,[22][23][24][25][26]: combinations of limonene or citral, or mixtures rich in these terpenes enhanced the pharmacological performance of chemotherapy or antiparasitic drugs in vitro and in vivo while minimizing their cytotoxic effects on normal host cells. The selectivity of these antiproliferative actions was ascribed to a possible bimodal activity of these terpenes, which may act as antioxidants under physiological conditions or switch to pro-oxidant activity in cells with increased susceptibility to oxidative stress (e.g., protozoa, yeast, or cancer cells) [23]. Accordingly, fraction F2 (rich in citral) showed a protective effect against oxidative stress, with a 31% decrease in mitochondrial superoxide basal levels (induced by collagen membrane solution), measured in J774A.1 murine macrophages using the fluorescent probe MitoSOX Red.…”

“…In this study, as an additive for collagen-GBR membranes, an optimized mixture of chlorhexidine with L. alba fractions enriched in bioactive terpenes (citral, caryophyllene oxide, and limonene) was investigated for its antimicrobial and bone regenerative effects. These terpenes have been extensively recognized as non-cytotoxic, wide-spectrum antimicrobial, immunomodulatory, and chemo-protective compounds [16,[21][22][23]. Herein, the citral-rich fraction (F2) and the limonene-rich fraction (F1) were shown to potentiate the anti-C. albicans activity of chlorhexidine on the surface of collagen membranes while increasing its regulated proinflammatory action and minimizing the toxic effects of the biocide on mammalian cells (i.e., a cytoprotective action).…”

D-Limonene: Promising and Sustainable Natural Bioactive Compound

“…Moreover, D-limonene is cardioprotective and gastroprotective [20,164], in addition to inhibiting the activity of cardiotoxicity biomarkers, such as alanine aminotransferase, lactate dehydrogenase, creatine kinase, creatine kinase MB, and the MAPK/NF-κB pathway; to reduce the damage of myocardial infarction, it also prevents cardiac histopathological changes [159,165]. Furthermore, oral D-limonene can increase local gastric mucosal defense mechanisms, such as mucus secretion, regulation of oxidative stress and inflammatory responses, and inhibition of the NF-κB pathway, to exert gastroprotective effects [17].…”

Lippia origanoides Essential Oil or Thymol in Combination with Fluconazole Produces Damage to Cells and Reverses the Azole-Resistant Phenotype of a Candida tropicalis Strain

“…This may provide an opportunity to discover EOs with antifungal activity. The aromatic species of plants of the Lippia (Verbenaceae) genus, have been studied in Colombia for their biological activities [ 33 , 34 , 35 ]. Lippia origanoides is a species of aromatic plant commonly known as “mountain oregano” and has been used by native communities for its medicinal properties [ 36 , 37 ].…”