Oligodendrocytes are key players in the montelukast-induced protection against stroke

Background. In the central nervous system, reparative therapies after injury should combine neuroprotection and remyelination. Montelukast, an anti-asthmatic drug, was shown to exert neuroprotection after brain ischemia by preserving brain fiber connectivity and white matter integrity, but whether this could occur by influencing myelin-producing oligodendrocytes remains to be elucidated. Here, to assess the effect of montelukast on oligodendrocyte precursor cells (OPCs), we induced ischemia by permanent middle cerebral artery occlusion (pMCAo) in reporter GPR17iCreERT2:CAG-eGreen florescent protein (GFP) mice, in which, upon tamoxifen treatment, OPCs expressing GPR17 become green and traceable for their entire life. Methods. Mice were subjected to pMCAo and treated with montelukast (10 mg/kg/day) or vehicle for 3 days, 2 and 8 weeks. Sham-operated mice were used as control. Electrophysiological analyses were performed weekly to evaluate functional outcomes. Oligodendrocyte dynamics and the anti-oxidant effect of montelukast were assessed by immunohistochemistry. The protective effects of montelukast on oligodendrocytes were corroborated by in vitro studies. Results. Electrophysiological analyses showed that, at all time points, pMCAo induced a significant decrease in the amplitude of field potentials, indicating a significant reduction in fiber connectivity. Conversely, in montelukast treated mice, the significant reduction of the amplitude of field potentials observed at week 4 and 5 was completely recovered and returned to baseline by week 5 and 7 after stroke, suggesting improved fibers reorganization and connectivity (Figure1). Immunofluorescence analyses showed that montelukast treatment was able to increase OPCs recruitment and proliferation during the sub-acute phase, and to promote their differentiation to mature oligodendrocytes at chronic phase of brain ischemia, 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. 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, a mechanism hitherto unexplored. These data raise the possibility of repositioning a safe, already marketed drug, with immediate advantages for patients suffering for stroke.