Repurposing memantine as an oral therapy for visceral leishmaniasis: identification of direct leishmanicidal activity...

Leishmaniasis, a neglected tropical disease caused by Leishmania spp., affects millions of individuals worldwide. Visceral leishmaniasis which represents the most severe disease type, is fatal if untreated. Current treatments are associated with various challenges, making drug repurposing a practical alternative. This study evaluated the NMDA receptor antagonist memantine for the treatment of Leishmania infantum.

To assess the effect of memantine against amastigote forms, peritoneal macrophages from BALB/c mice were infected with Leishmania infantum promastigotes, and the proportion of infected macrophages was assessed via light microscopy and expressed as an infection index. In a murine model of visceral leishmaniasis, the efficacy of memantine was evaluated by using two different treatment schemes (short-term and long-term), and the parasite load in the liver and spleen was quantified by using a limiting dilution assay. Meglumine antimoniate, which is the reference drug used in clinical settings for leishmaniasis treatment, was selected as the positive control. The immunological profile of uninfected and infected BALB/c mice (either treated or not treated with memantine or the reference drug) was evaluated in splenocyte cultures (with or without stimulation with the Leishmania infantum antigen).

In vitro, memantine demonstrated significant activity against intracellular amastigotes (IC₅₀ = 5.49 ± 0.11 μM; SI = 603.64). In vivo, the oral administration of memantine (3 and 6 mg/kg/day) in BALB/c mice reduced the parasite burden in the liver and spleen by >99%, thereby outperforming lower doses and conventional meglumine antimoniate treatment. Parasite clearance was consistent with nitrosative stress-independent immunomodulation and was associated with a shift towards a Th1-dominant immune response (involving increased IFN-γ/IL-10 levels), in addition to Th2 and Th17 activation (including IL-2, IL-4, and IL-17), thus promoting parasite control and granuloma formation. Memantine was observed to be safe and well-tolerated; additionally, it demonstrated immunomodulatory effects by rebalancing the immune response to favor parasite clearance.

Memantine exhibits dual effects, including direct antiparasitic activity and host-directed immunomodulation. These findings support its potential use as a repurposed candidate for treating visceral leishmaniasis and reinforce the value of drug repositioning as a strategy to accelerate the development of safe and effective therapies.