Abstract
Toxoplasmosis is one of the most prevalent and neglected zoonotic global diseases caused by Toxoplasma gondii. The current pharmacological treatments show clinical limitations, and therefore, the search for new drugs is an urgent need in order to eradicate this infection. Due to their intrinsic biological activities, β-carboline (βC) alkaloids might represent a good alternative that deserves further investigations. In this context, the in vitro anti-T. gondii activity of three βCs, harmine (1), 2-methyl-harminium (2), and 9-methyl-harmine (3), was evaluated herein. Briefly, the three alkaloids exerted direct effects on the parasite invasion and/or replication capability. Replication rates of intracellular treated tachyzoites were also affected in a dose-dependent manner, at noncytotoxic concentrations for host cells. Additionally, cell cycle analysis revealed that both methyl-derivatives 2 and 3 induce parasite arrest in S/M phases. Compound 3 showed the highest irreversible parasite growth inhibition, with a half maximal inhibitory concentration (IC50) value of 1.8 ± 0.2 μM and a selectivity index (SI) of 17.2 at 4 days post infection. Due to high replication rates, tachyzoites are frequently subjected to DNA double-strand breaks (DSBs). This highly toxic lesion triggers a series of DNA damage response reactions, starting with a kinase cascade that phosphorylates a large number of substrates, including the histone H2A.X to lead the early DSB marker γH2A.X. Western blot studies showed that basal expression of γH2A.X was reduced in the presence of 3. Interestingly, the typical increase in γH2A.X levels produced by camptothecin (CPT), a drug that generates DSB, was not observed when CPT was co-administered with 3. These findings suggest that 3 might disrupt Toxoplasma DNA damage response.
Highlights
Toxoplasma gondii is an obligate intracellular protozoan parasite that belongs to the phylum Apicomplexa, which infects a wide range of warm-blooded animals, causing toxoplasmosis
Toxoplasmosis is usually asymptomatic in immunocompetent persons (Alday and Doggett, 2017) and leads to chronic infection, with cyst formation mainly in the central nervous system (CNS) (Martins-Duarte et al, 2006)
To establish the operational concentration range for the antiparasitic studies, cytotoxicity of 1–3 was tested on host cells (Vero)
Summary
Toxoplasma gondii is an obligate intracellular protozoan parasite that belongs to the phylum Apicomplexa, which infects a wide range of warm-blooded animals, causing toxoplasmosis. The quite high binding affinity of the latter βCs and the ATP-binding domain of Plasmodium heat shock protein 90 (Hsp90) would be a key step in the mechanism of action These compounds showed a significant reduction of parasitemia in vivo, exerting a synergistic effect when co-administered with other existing antimalarial drugs (Shahinas et al, 2012; Bayih et al, 2016). We found that 1, norharmane, and harmane inhibited T. gondii invasion and replication in a dosedependent manner, with 1 being the most effective compound in blocking a parasite’s growth (Alomar et al, 2013) In this context and based on the fact that methyl-substituted βCs show enhanced biological and/or antimicrobial properties (Dai et al, 2018), the in vitro antitoxoplasmic activity of 2-methyl-harminium (2) and 9-methyl-harmine (3) (Figure 1) was evaluated . The effect on parasite invasion, replication, and growth processes was assessed
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