Terminalia albida treatment improves survival in experimental cerebral malaria through reactive oxygen species scavenging and anti-inflammatory properties

Abstract

BackgroundThe development of Plasmodium resistance to the last effective anti-malarial drugs necessitates the urgent development of new anti-malarial therapeutic strategies. To this end, plants are an important source of new molecules. The objective of this study was to evaluate the anti-malarial effects of Terminalia albida, a plant used in Guinean traditional medicine, as well as its anti-inflammatory and antioxidant properties, which may be useful in treating cases of severe malaria.MethodsIn vitro antiplasmodial activity was evaluated on a chloroquine-resistant strain of Plasmodium falciparum (K-1). In vivo efficacy of the plant extract was measured in the experimental cerebral malaria model based on Plasmodium berghei (strain ANKA) infection. Mice brains were harvested on Day 7–8 post-infection, and T cells recruitment to the brain, expression levels of pro- and anti-inflammatory markers were measured by flow cytometry, RT-qPCR and ELISA. Non-malarial in vitro models of inflammation and oxidative response were used to confirm Terminalia albida effects. Constituents of Terminalia albida extract were characterized by ultra‐high performance liquid chromatography coupled with high resolution mass spectrometry. Top ranked compounds were putatively identified using plant databases and in silico fragmentation patterns.ResultsIn vitro antiplasmodial activity of Terminalia albida was confirmed with an IC50 of 1.5 μg/mL. In vivo, Terminalia albida treatment greatly increased survival rates in P. berghei-infected mice. Treated mice were all alive until Day 12, and the survival rate was 50% on Day 20. Terminalia albida treatment also significantly decreased parasitaemia by 100% on Day 4 and 89% on Day 7 post-infection. In vivo anti-malarial activity was related to anti-inflammatory properties, as Terminalia albida treatment decreased T lymphocyte recruitment and expression of pro-inflammatory markers in brains of treated mice. These properties were confirmed in vitro in the non-malarial model. In vitro, Terminalia albida also demonstrated a remarkable dose-dependent neutralization activity of reactive oxygen species. Twelve compounds were putatively identified in Terminalia albida stem bark. Among them, several molecules already identified may be responsible for the different biological activities observed, especially tannins and triterpenoids.ConclusionThe traditional use of Terminalia albida in the treatment of malaria was validated through the combination of in vitro and in vivo studies.

Variation in chemical composition and antimalarial activities of two samples of Terminalia albida collected from separate sites in Guinea

“…In this model, untreated mice died by Day 9 post-infection whereas T. albida treated-mice were all still alive by Day 12 post-infection. Such activity was associated to anti-inflammatory and anti-oxidant properties of T. albida in this study [14].…”

“…Only the stem bark of T. avicennioides showed a significant inhibition of 82% of P. berghei parasitemia at Day 5 post-infection at 100 mg/kg [11]. As we have previously shown, the capacity of TaD to limit death in P. bergheiinfected mice may be due to its anti-inflammatory and antioxidant properties [14]. In this model, mice death is attributed to preferential sequestration of leukocytes in the brain, vascular obstruction, endothelial activation and neuroinflammation [19,27].…”

“…Its antimalarial properties have been previously demonstrated both in vitro and in vivo. In vitro, two studies have shown that T. albida has antiparasitic activities against the chloroquine-resistant strain Pf-K1 with half maximal inhibitory concentrations (IC 50 ) of 0.6 μg/mL [13] and 1.5 μg/mL [14]. In the latest study, our team also reported high antimalarial activity in a murine model of experimental cerebral malaria.…”

Malaria in Guinean Rural Areas: Prevalence, Management, and Ethnotherapeutic Investigations in Dionfo, Sub-Prefecture of Labe

“…However, T. albida (cited 274 times) was more popular as an antimalarial than T. macroptera (cited 37 times). It is noteworthy that in a previous study, T. macroptera was one of the plant species most cited as an antimalarial drug on the Guinean scale [1,19].…”

Plants of the Genus Terminalia: An Insight on Its Biological Potentials, Pre-Clinical and Clinical Studies

“…extract against the important parasites ( Table 9 ). Camara and team reported antimalaria activity of Terminalia albida Scott-Elliot bark extract against Plasmodium falciparum with low IC 50 as 1.5 µg/mL ( Camara et al., 2019 ). Moreover, an increase in the survival rate of mice infected with the P. berghei was detected when they were treated with the bark extract of Terminalia albida Scott-Elliot ( Camara et al., 2019 ) and Terminalia avicennioides Guill.…”