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  • It is also possible that adrenoceptor activation may inhibit

    2023-01-16

    It is also possible that α2-adrenoceptor activation may inhibit glutamate accumulation by upregulating the glutamate-buffering activity of Müller Seratrodast through EAAT1 or adjusting EAAT2 in bipolar cells, as well as the NMDA receptor. Therefore, we investigated whether topical administration of brimonidine could modulate glutamate transporters, including EAAT1 and EAAT2, and also the glutamate NMDA receptor, in a chronic ocular hypertension model.
    Materials and methods
    Results
    Discussion In this work, chronically elevated IOP induced glial activation and marked RGC loss with increased expression of NMDA receptor especially in the GCL and EAAT2. EAAT1 expression remained stable throughout the period of chronic ocular hypertension. α2-adrenergic treatment attenuated glial activation and RGC loss, stimulating the EAAT1 expression, and suppressing NMDA receptor and EAAT2. With regard to excitotoxicity as the pathogenesis of glaucoma, we did not confirm a direct relationship between EAAT1 change or RGC apoptosis and glutamate levels in this study. However, measuring intravitreal and retinal glutamate levels is a difficult and unreliable process. Several studies have been unable to reproduce intravitreal glutamate levels from experimental animals, such as retinal ischemia and a glaucoma model (Almasieh et al., 2012). To date, experimental work in this area has progressed slowly (Almasieh et al., 2012; Dalton, 2001). A critical limitation in the basic study of excitotoxicity is that research has usually focused only on the neuronal response, but it is also important to pay attention to glial cells, which play key roles in the glutamate homeostasis. Investigations of the glutamate transporter and receptor are critical aspects in the study of excitotoxicity as a part of glaucoma pathogenesis. Therefore, we focused on the role of glutamate transporters of glial cells as well as the glutamate receptor in glaucoma, and how an α2 agonist affects them. In the normal retina, GFAP is expressed in the end feet of the Müller cells and astrocytes in the nerve fiber layer (Bringmann et al., 2006; Vidal et al., 2010). In the current study, chronic IOP elevation stimulated GFAP expression spanning the entire retina. Upregulation of the GFAP is a sensitive early indicator of retinal stress (Bringmann and Wiedemann, 2012; Lewis and Fisher, 2003). In cauterized eyes, EAAT1 expression levels increased slightly 1 week after cauterization and decreased after that, although these changes were not statistically significant within the experimental time period. In experimental glaucoma, Müller cells do not appear to sustain increased EAAT1 activity. Cell depolarization due to increased extracellular potassium (which occurs in glaucoma) substantially lowers the uptake rate of glutamate in Müller cells (Ryan et al., 2004). Because of the inefficient uptake of glutamate, a stable EAAT1 level in glaucoma seems to suggest insufficient glutamate uptake by Müller cells, which might result in significant glutamate uptake by RGCs (Holcombe et al., 2008; Martin et al., 2002). Suppression of the Müller cell glutamate transporter caused more than a three-fold increase in the vitreal concentration of glutamate (Vorwerk et al., 2000). Deletion of EAAT1 in mice leads to optic nerve degeneration (Harada et al., 2007). In one study using a rat glaucoma model, however, EAAT1 immunoreactivity was upregulated (Woldemussie et al., 2004). The extent of IOP increase seems to be higher in that study compared to our study, even though we cannot explain the definite reason for this discrepancy. Elevation of extracellular glutamate results in excessive activation of NMDA-type glutamate receptors in neuron. In this study, we demonstrated that chronically elevated IOP increased GluN1 subunit expression. Because NMDA-type glutamatergic channels are highly permeable to calcium ions, overactivation of those is especially harmful to neuron (Lipton and Rosenberg, 1994; Sucher et al., 1990). In the current study, we showed that apoptotic cell death indicated by TUNEL staining was increased prominently in the GCL following elevation of IOP, and that it colocalized with GluN1 subunit expression. Thus, the increase in GluN1 subunit after cauterization could have relevance to the degeneration of RGCs in the glaucomatous rat retina.