Montelukast, a safe anti-asthmatic drug, protects against stroke by improving anti-oxidant defence of oligodendrocyte precursor cells

Montelukast was shown to exert neuroprotection after brain ischemia by preserving white matter integrity, but whether this could occur by influencing myelin-producing oligodendrocytes remains unexplored. Here, we assess the effect of montelukast on oligodendrocyte precursor cells (OPCs), in a model of permanent cerebral ischemia (pMCAo) in reporter florescent protein (GFP) mice, in which, upon tamoxifen treatment, OPCs expressing GPR17 become green and traceable for their entire life. Mice subjected to pMCAo were treated with montelukast (10 mg/kg/day) or vehicle for 3 days, 2 and 8 weeks. Electrophysiological analyses were performed weekly to evaluate functional outcomes. Oligodendrocyte dynamics were assessed by immunohistochemistry and the protective effects of montelukast on oligodendrocytes corroborated in vitro. Electrophysiological analyses showed that pMCAo induced a significant decrease in the amplitude of field potentials, indicating a reduction in fiber connectivity. Conversely, in montelukast-treated mice, the reduction of the amplitude of field potentials observed at week 4 and 5 was recovered and returned to baseline by week 5 and 7 after stroke, suggesting improved fibers reorganization. Immunofluorescence analyses showed that montelukast treatment increases OPCs recruitment and proliferation and promotes their differentiation to mature oligodendrocytes suggesting a link between OPCs activation, maturation and fiber connectivity. Moreover, montelukast treatment significantly increased the anti-oxidant defense of OPCs as evident from the enhanced number of GFP+-oligodendrocytes expressing heme oxygenase 1 (HO-1) 3 days after MCAo. In vitro, montelukast was able to counteract TNF-α-induced apoptosis and defective OPCs maturation. We are currently evaluating the effect of montelukast in protecting OPCs by oxidative stress. In conclusion, we demonstrated that montelukast improves long-term functional recovery after brain ischemia by enhancing the recruitment, survival and maturation of OPCs towards myelinating stage through anti-oxidant capacity. These data raise the possibility of repositioning an already marketed drug with immediate advantages for patients suffering for stroke.