Exploring the leishmanicidal potential of terpenoids: a comprehensive review on mechanisms of cell death

Abstract

Leishmaniasis is a neglected tropical disease with a wide spectrum of clinical manifestations, ranging from visceral to cutaneous, with millions of new cases and thousands of deaths reported each year. The species of Leishmania and the immune response of the host determine the severity of the disease. Leishmaniasis remains challenging to diagnose and treat, and there is no vaccine available. Several studies have been conducted on the use of herbal medicines for the treatment of leishmaniasis. Natural products can provide an inexhaustible source of chemical diversity with therapeutic potential. Terpenes are a class of natural products derived from a single isoprene unit, a five-carbon compound that forms the basic structure of isoprenoids. This review focuses on the most important and recent advances in the treatment of parasites of the genus Leishmania with different subclasses of terpenes. Several mechanisms have been proposed in the literature, including increased oxidative stress, immunomodulatory role, and induction of different types of parasite cell death. However, this information needs to be brought together to provide an overview of how these compounds can be used as therapeutic tools for drug development and as a successful adjuvant strategy against Leishmania sp.

Keywords: Leishmania; immunomodulation; oxidative stress; terpenes; treatment.

Figure 1

Chemical structures of the monoterpenes that showed activity against Leishmania spp.

Figure 2

Monoterpenes exert leishmanicidal activity by disrupting parasite metabolism. Monoterpenes alter the metabolism of Leishmania spp. by increasing lipid peroxidation, ROS, thiol and ATP depletion, leading to mitochondrial damage and phosphatidylserine exposure in promastigotes. In hamsters (Mesocricetus auratus), thymol reduced the number of amastigotes in the liver and kidneys, and carvacrol reduced the local inflammatory response.

Figure 3

Chemical structures of the sesquiterpenes that showed activity against Leishmania spp. The figure shows the chemical structure of all sesquiterpenes present in the text that showed antileishmanial activity.

Figure 4

Sesquiterpene compounds show immunomodulatory activity against Leishmania spp. The representative scheme shows the activity of the sesquiterpene compounds against L. amazonensis and L. infantum. In the J774 cell line infected with Leishmania spp, the administration of sesquiterpene compounds promoted the increase of ROS, NO, IL-12 and TNF-a. In dogs infected with L. infantum, treatment with sesquiterpenes increased pro-inflammatory responses, leading to a balance of Th1/Th2 patterns and reduced parasite load.

Figure 5

Diterpenes showed antileishmanial activity by causing change in parasite morphology, increased ROS and cytosolic calcium, plasma membrane permeability, mitochondrial depolarization, phosphatidylserine exposure, autophagy, and DNA fragmentation in promastigote forms. In peritoneal macrophages and THP-1 cells infected with Leishmania spp, iron uptake, pro-inflammatory cytokines and downregulation of Nrf2 were responsible for the reduction in the number of amastigotes per cell. In vivo diterpenes promote Th1/Th2 balance leading to reduction in lesion size and improved healing.

Figure 6

Structures of the diterpenes that showed activity against Leishmania spp. The figure shows the chemical structure of all diterpenes present in the text that showed antileishmanial activity.

Figure 7

Chemical structures of the triterpenes that showed activity against Leishmania spp.

Figure 8

Triterpenes exert activity on the Leishmania Hsp90 protein leading to ATP depletion in promastigotes. In peritoneal macrophages and infected THP-1 cells, triterpene compounds increased IL-12 and NO₂- and decreased IL-10, leading to elimination of intracellular amastigotes. In BALB/C mice and hamsters, triterpene compounds increased Th1 cytokines and decreased Th2 cytokines, leading to parasite clearance in the spleen and liver of infected animals.