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This study aimed to investigate the in vitro antioxidant activity of the novel anticonvulsant levetiracetam and benzodiazepine clonazepam. To do this, the mice brain homogenates were incubated with levetiracetam (50, 100 or 200 g/ml) or clonazepam (50, 100 or 200 g/ml), and then, submitted to heating at 37°C for 1 h. Ascorbic acid (vitamin C, 200 g/ml) was used as reference antioxidant drug. The markers of oxidative stress, such as lipid peroxidation, nitrite-nitrate content, catalase activity, and reduced glutathione (GSH) levels, were measured in brain homogenates. The group submitted to the heating-induced oxidative stress showed an increase in lipid peroxidation, nitrite-nitrate content, and catalase activity. Previous incubation with levetiracetam and clonazepam, mainly at lower doses (50 and 100 g/ml), and similarly to vitamin C, prevented these pro-oxidative changes, reducing the lipid peroxidation, nitrite-nitrate contents and catalase activity, and increasing GSH levels. These findings demonstrate antioxidant properties of levetiracetam and clonazepam, and help to elucidate the role of protection against oxidative stress in the neuroprotective mechanism of antiepileptic drugs.

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We postulated that dimethyl fumarate (DMF), an activator of the Nuclear Factor Erythroid 2-related factor 2 (Nrf2) pathway, exerts neuroprotective effects against depression-like behaviors through astrocytes and microglia modulation. To ascertain our hypothesis and define the mechanistic pathways involved in effect of DMF on neuroinflammation, we used the depression model induced by Chronic Unpredictable Mild Stress (CUMS), in which, the mice were exposed to stressful events for 28 days and from the 14th day they received DMF in the doses of 50 and 100 mg / kg or fluoxetine 10 mg / kg or saline. On the 29th day, the animals were subjected to behavioral tests. Microglia (Iba1) and astrocytes (GFAP) markers expressions were evaluated by immunofluorescence analyzes and the cytokines TNF-α and IL-Iβ by immunoenzymatic assay. In addition, computational target prediction, 3D protein structure prediction and docking calculations were performed with monomethyl fumarate (DMF active metabolite) and the Kelch-like ECH associated protein-1 and hydroxycarboxylic acid receptor 2 (HCAR2), which suggested that these could be the probable targets related protective effects. CUMS induced anxiety- and depressive-like behaviors, cognitive deficit, decreased GFAP and increased Iba1, TNF-α and IL-Iβ expression in the hippocampus. These alterations were reversed by DMF. Thus, it is suggested that one of the mechanisms involved in the antidepressant effect of DMF is neuroinflammatory suppression, through the signaling pathway HCAR2 / Nrf2. However, more studies must be performed to better understand the molecular mechanisms of this drug.

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