Neurological aspects of Leishmaniasis via immunological mechanism and evaluation of boron for neuroinflammatory-based antileishmanial therapy

Leishmaniasis is a neglected tropical disease, caused by the protozoan parasites of the genus Leishmania (L.), and is transmitted by the bite of phlebotomine sandflies. It is endemic in over 98 countries per year, including Turkey and its subcontinental region. There are several studies on central nervous system infection to show that Leishmania can cross the blood brain barrier, resulting in neurological manifestations, known as "cerebral leishmaniasis". Accordingly, this study highlighted three notions, including (i) the investigation of how L. parasites are transmitted into the brain via macrophages, and the mechanism underlying the inflammatory responses on both macrophages and astrocytes in the infection model, (ii) novel flow cytometric approach for quantification of L.-infected macrophages, and (iii) the antileishmanial efficacy and anti-neuroinflammatory activity of Sodium Perborate Tetrahydrate (SPT) on L. infantum, L.-infected macrophages and -astrocytes in in vitro cultures. According to the results, when the non-infected astrocytes co-cultured with or without L.-infected macrophages, the percentage of L. infantum was decreased to 24.88% and 7%, respectively, compared to the negative control, indicating a lower infection rate than the co-culture. Likewise, upon 75-200 µM of SPT treatment, L. infantum promastigotes indicated a significant reduction in growth, without any toxicity on macrophages and astrocytes. Furthermore, a reduction in the mitochondrial membrane potential was detected after SPT treatment through apoptotic-like cell death, cell-cycle arrest, and astrocyte-activated-immune response. Besides, a decrease in the ROS and oxidative stress levels were determined in the infected cells, which was also investigated by the qPCR analysis. Conclusively, it is the first study to emphasize the communication between L.-infected macrophages and astrocytes regarding the parasite load, and inflammatory response against cell-specific infections. The antileishmanial efficacy together with the neuroinflammatory-based SPT therapy was shown on L. infantum promastigotes, L.-infected macrophages, and -astrocytes. The promising efficacy of the SPT in vitro L.-infection model highlights the potential of antileishmanial therapy in the future in further in vivo studies and clinical studies. Keywords: Leishmania, Leishmaniasis, Macrophage, Astrocyte, Neuroinflammation