Could Fluoxetine Confer a Favourable Immuno-Inflammatory Profile in a Murine Model of Acute Toxoplasmosis?

Acute toxoplasmosis could be life-threatening, as the body is overwhelmed both by the rapidly replicating tachyzoites and the immunopathological sequelae of the robust immune response with no satisfactory treatment or vaccine available to date. Fluoxetine, a selective serotonin reuptake inhibitor, is recently repurposed to control cytokine storm in certain clinical settings. In this study, an animal model of acute toxoplasmosis was established using the virulent RH strain. To compare their therapeutic effects, either spiramycin or fluoxetine was administered for 5 days starting from the day of infection. To assess its prophylactic effects, fluoxetine was started 2 weeks before induction of the infection. It was found that fluoxetine as well as spiramycin achieved comparable reduction of the tachyzoite counts with prominent deleterious morphological effects on the tachyzoites detected by scanning electron microscopy. Both drugs improved the histopathological changes with superior effect of fluoxetine, particularly in the brain. Fluoxetine attenuated substantially the inflammatory response through the reduction of TNF-α, IL-4 and MCP-1 levels. Prophylactic fluoxetine administration also induced improvement of the redox status. Moreover, fluoxetine exhibited superior effect in reversal of infection-induced modulation of apoptosis and vascular dysfunction in the brain via significantly reducing the levels of p21 and endocan, respectively. Fluoxetine also upregulated the levels of growth differentiation factor 15 in the spleen, partly accounting for the limitation of the immunopathology. In conclusion, fluoxetine showed antiparasitic activity comparable to that of spiramycin, and displayed superior anti-inflammatory, immunomodulatory, vascular protective and pro-apoptotic effects, leading to better survival in acute murine toxoplasmosis.