title: α2-Adrenergic modulation of the glutamate receptor and transporter function in a chronic ocular hypertension model.
abstract: Excitotoxicity, glutamate-induced toxic effects to retinal ganglion cells (RGCs), is one of several mechanisms of RGC loss suggested in glaucoma. In this study, we focused on the role of glutamate transporter of glial cells as well as N-methyl-d-aspartate (NMDA) receptor with regard to glutamate toxicity in glaucoma. We also investigated whether α2-adrenoceptor activation could modulate glutamate transporters and NMDA receptors in a chronic ocular hypertension model. Brimonidine 0.15% was administered topically to the eyes of experimental glaucoma and control animals twice daily. After 8 weeks of intraocular pressure (IOP) elevation, staining with terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) revealed an increase in the ganglion cell layer, and the number of TUNEL-positive cells was reduced by brimonidine treatment (P<0.05). Animals with experimentally induced glaucoma exhibited an increase in retinal stress marker glial fibrillary acidic protein (GFAP) immunoreactivity; brimonidine treatment reduced GFAP. Excitatory amino acid transporter 1(EAAT1) expression remained stable throughout the period of chronic ocular hypertension. α2-Adrenergic treatment upregulated EAAT1 protein levels (P<0.05). NMDA receptor (GluN1) expression was stimulated by chronic elevation of IOP, and GluN1-positive cells in ganglion cell layer were co-localized with TUNEL staining. Brimonidine administration suppressed GluN1 levels (P<0.05). These results indicate that brimonidine decreased RGC apoptosis, upregulating EAAT1 and downregulating NMDA receptors. We suggest that topical brimonidine treatment may decrease the glutamate excitotoxicity through modulation of glutamate transporter and NMDA receptor in glaucoma.
authors: Department of Ophthalmology and Visual Science, Seoul St. Mary's Hospital, College of MedicineThe Catholic University of Korea, Seoul, Korea.
authors: Kyoung In
authors: KI
authors: Jung
authors: Department of Ophthalmology and Visual Science, Seoul St. Mary's Hospital, College of MedicineThe Catholic University of Korea, Seoul, Korea.
authors: Jie Hyun
authors: JH
authors: Kim
authors: Department of Ophthalmology and Visual Science, Seoul St. Mary's Hospital, College of MedicineThe Catholic University of Korea, Seoul, Korea. Electronic address: ckpark@catholic.ac.kr.
authors: Chan Kee
authors: CK
authors: Park
mesh_terms: D058647:Adrenergic alpha-2 Receptor Agonists / Q000008:administration & dosage / Q000627:therapeutic use*; D000818:Animals; D001692:Biological Transport; D000068438:Brimonidine Tartrate / Q000008:administration & dosage / Q000627:therapeutic use*; D002908:Chronic Disease; D027341:Excitatory Amino Acid Transporter 1 / Q000378:metabolism; D005901:Glaucoma / Q000188:drug therapy* / Q000378:metabolism; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D018698:Glutamic Acid / Q000378:metabolism*; D007429:Intraocular Pressure / Q000187:drug effects; D008297:Male; D017207:Rats, Sprague-Dawley; D018341:Receptors, Adrenergic, alpha-2 / Q000378:metabolism*; D017470:Receptors, Glutamate / Q000378:metabolism*
chemical_list: D058647:Adrenergic alpha-2 Receptor Agonists; D027341:Excitatory Amino Acid Transporter 1; D005904:Glial Fibrillary Acidic Protein; D018341:Receptors, Adrenergic, alpha-2; D017470:Receptors, Glutamate; C493392:Slc1a3 protein, rat; D018698:Glutamic Acid; D000068438:Brimonidine Tartrate
keywords: Brimonidine; Brimonidine d-tartrate (Prochem CID 6917831); EAAT1; Glaucoma; GluN1; Glutamate excitotoxicity; N-methyl-d-aspartic acid (Pubchem CID 22880); Retinal ganglion cell