montelukast and Ocular-Hypertension

Glaucoma is the second leading cause of blindness worldwide. This multifactorial, neurodegenerative group of diseases is characterized by the progressive loss of retinal ganglion cells (RGCs) and their axons, leading to irreversible visual impairment and blindness. There is a huge unmet and urging need for the development of new and translatable strategies and treatment options to prevent this progressive loss of RGC. Accumulating evidence points towards a critical role of neuroinflammation, in particular microglial cells, in the pathogenesis of glaucoma. Leukotrienes are mediators of neuroinflammation and are involved in many neurodegenerative diseases. Therefore, we tested the leukotriene receptors CysLT1R/GPR17-selective antagonist Montelukast (MTK) for its efficacy to modulate the reactive state of microglia in order to ameliorate RGCs loss in experimental glaucoma. Ocular hypertension (OHT) was induced unilaterally by injection of 8 μm magnetic microbead (MB) into the anterior chamber of female Brown Norway rats. The contralateral, untreated eye served as control. Successful induction of OHT was verified by daily IOP measurement using a TonoLab rebound tonometer. Simultaneously to OHT induction, one group received daily MTK treatment and the control group vehicle solution by oral gavage. Animals were sacrificed 13-15 days after MB injection. Retina and optic nerves (ON) of OHT and contralateral eyes were analyzed by immunofluorescence with specific markers for RGCs (Brn3a), microglial cells/macrophages (Iba1 and CD68), and cysteinyl leukotriene pathway receptors (CysLT1R and GPR17). Protein labeling was documented by confocal microscopy and analyzed with ImageJ plugins. Further, mRNA expression of genes of the inflammatory and leukotriene pathway was analyzed in retinal tissue. MTK treatment resulted in a short-term IOP reduction at day 2, which dissipated by day 5 of OHT induction in MTK treated animals. Furthermore, MTK treatment resulted in a decreased activation of Iba1

Topics: Acetates; Animals; Antigens, CD; Antigens, Differentiation, Myelomonocytic; Biomarkers; Calcium-Binding Proteins; Cell Survival; Cyclopropanes; Disease Models, Animal; Electroretinography; Female; Gene Expression Regulation; Intraocular Pressure; Leukotriene Antagonists; Microfilament Proteins; Microglia; Microscopy, Confocal; Microscopy, Fluorescence; Ocular Hypertension; Quinolines; Rats; Rats, Inbred BN; Real-Time Polymerase Chain Reaction; Receptors, G-Protein-Coupled; Receptors, Leukotriene; Retina; Retinal Ganglion Cells; RNA, Messenger; Sulfides; Tonometry, Ocular; Transcription Factor Brn-3B