Inhibition of the cysteinyl leukotriene pathways increases survival of RGCs and reduces microglial activation in ocular hypertension

Autor: Anja-Maria Ladek, C. Strohmaier, Alexandra Kaser-Eichberger, Barbara Bogner, Karolina Motloch, Falk Schroedl, Christian Runge, Daniela Bruckner, Susanne M. Brunner, Julia Preishuber-Pfluegl, Andreas Koller, Herbert A. Reitsamer, Andrea Trost, Ludwig Aigner
Rok vydání: 2021
Předmět:
Cyclopropanes
Retinal Ganglion Cells
genetic structures
Acetates
Pharmacology
Receptors
G-Protein-Coupled
Rats
Inbred BN
Medicine
Leukotriene
Microscopy
Confocal
Microglia
Microfilament Proteins
Transcription Factor Brn-3B
Sensory Systems
medicine.anatomical_structure
Quinolines
Female
medicine.drug
Cell Survival
Antigens
Differentiation
Myelomonocytic
Sulfides
Real-Time Polymerase Chain Reaction
Neuroprotection
Retinal ganglion
Retina
Tonometry
Ocular
Cellular and Molecular Neuroscience
Antigens
CD
Electroretinography
Animals
RNA
Messenger
Intraocular Pressure
Montelukast
Neuroinflammation
Receptors
Leukotriene
business.industry
Leukotriene receptor
Calcium-Binding Proteins
eye diseases
Rats
Disease Models
Animal
Ophthalmology
Gene Expression Regulation
Microscopy
Fluorescence
Leukotriene Antagonists
Ocular Hypertension
sense organs
business
Biomarkers
Zdroj: Experimental Eye Research. 213:108806
ISSN: 0014-4835
Popis: 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 immunohistochemistry 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+ microglial cells in the retina and ON, and in a significantly increased RGC survival in OHT eyes. Within the retina, GPR17 and CysLT1R expression was demonstrated in single RCGs and in microglial cells respectively. Further, increased mRNA expression of pro-inflammatory genes was detected in OHT induced retinas. In the ON, OHT induction increased the number of GPR17+ cells, showing a significant reduction following MTK treatment. This study shows for the first time a significantly increased RGC survival in an acute OHT model following treatment with the leukotriene receptor antagonist MTK. These results strongly suggest a neuroprotective effect of MTK and a potential new therapeutic strategy for glaucoma treatment.
Databáze: OpenAIRE
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