α2-Adrenergic modulation of the glutamate receptor and transporter function in a chronic ocular hypertension model.

Published on Oct 15, 2015in European Journal of Pharmacology4.432
· DOI :10.1016/J.EJPHAR.2015.08.035
Kyoung In Jung13
Estimated H-index: 13
(Catholic University of Korea),
Jie Hyun Kim15
Estimated H-index: 15
(Catholic University of Korea),
Chan Kee Park28
Estimated H-index: 28
(Catholic University of Korea)
Sources
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.
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References49
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#1Hae-Young Lopilly Park (Catholic University of Korea)H-Index: 30
#2Jie Hyun Kim (Catholic University of Korea)H-Index: 15
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Background Dendrites of retinal ganglion cells (RGCs) synapse with axon terminals of bipolar cells in the inner plexiform layer (IPL). Changes in RGC dendrites and synapses between bipolar cells in the inner retinal layer may critically alter the function of RGCs in glaucoma. Recently, synaptic plasticity has been observed in the adult central nervous system, including the outer retinal layers. However, few studies have focused on changes in the synapses between RGCs and bipolar cells in glaucom...
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#1Makoto AiharaH-Index: 49
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Purpose: To investigate the effect of hyperbaric pressure on purified retinal ganglion cells (RGCs) and the additive effect of hyperbaric pressure on glutamate-induced RGC death. Methods: An RGC primary culture from 8-day-old Wistar rats was prepared and cultured in a hyperbaric chamber. The RGC survival rate under various pressure conditions and with 5 or 25 µM of glutamate stimulation was determined and compared with that of RGCs under isobaric conditions. First, RGCs were cultured at atmosphe...
#2Jie Chen (Fudan University)H-Index: 4
DBA/2J mouse has been used as a model for spontaneous secondary glaucoma. Here, we investigated changes in expression of NMDA receptor (NMDAR) subunits and Cdk5/p35/NMDAR signaling in retinas of DBA/2J mice using Western blot technique. The protein levels of NR1 and NR2A subunits in retinas of DBA/2J mice at all ages (6–12 months) were not different from those in age-matched C57BL/6 mice. In contrast, the protein levels of NR2B subunits, in addition to age-dependent change, significantly increas...
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#1Yuki Fujita (Osaka University)H-Index: 19
#2A Sato (Osaka University)H-Index: 1
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It is well known that axons of the adult mammalian central nervous system have a very limited ability to regenerate after injury. Therefore, the neurodegenerative process of glaucoma results in irreversible functional deficits, such as blindness. Brimonidine (BMD) is an alpha2-adrenergic receptor agonist that is used commonly to lower intraocular pressure in glaucoma. Although it has been suggested that BMD has neuroprotective effects, the underlying mechanism remains unknown. In this study, we ...
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#1Kyoung In Jung (Catholic University of Korea)H-Index: 13
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Neurodegeneration is an important component of diabetic retinopathy, with increasing evidence that retinal ganglion cell (RGC) death occurs early in diabetes. We investigated the effects of cilostazol, which has been widely used to manage diabetic complications, on retinal ganglion cell death in the diabetic retina. Four-week-old Otsuka Long-Evans Tokushima fatty (OLETF) rats and Long-Evans Tokushima Otsuka (LETO) rats as matched nondiabetic controls were treated with daily oral cilostazol at 30...
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Muller cells, the principal glial cells of the retina, support the synaptic activity by the uptake and metabolization of extracellular neurotransmitters. Muller cells express uptake and exchange systems for various neurotransmitters including glutamate and γ-aminobutyric acid (GABA). Muller cells remove the bulk of extracellular glutamate in the inner retina and contribute to the glutamate clearance around photoreceptor terminals. By the uptake of glutamate, Muller cells are involved in the shap...
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Elevated eye pressure is the main risk factor for glaucoma, and intraocular pressure rises when the balance between aqueous humor formation and outflow resistance is compromised. In a normal eye there is a precise tune of aqueous outflow under the fine control of ciliary body and trabecular meshwork. Current pharmacological therapies for lowering the intraocular pressure in glaucoma include increasing aqueous humor outflow and suppression of aqueous humor production. However, most of antiglaucom...
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Glutamate excitotoxicity-induced oxidative stress have been linked to mitochondrial dysfunction in retinal ischemia and optic neuropathies including glaucoma. Brimonindine (BMD), an alpha 2-adrenergic receptor agonist, contributes to the neuroprotection of retinal ganglion cells (RGCs) against glutamate excitotoxicity or oxidative stress. However, the molecular mechanisms of BMD-associated mitochondrial preservation in RGC protection against glutamate excitotoxicity-induced oxidative stress foll...
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Abstract Glaucoma is a group of diseases characterized by progressive optic nerve degeneration that results in visual field loss and irreversible blindness. A crucial element in the pathophysiology of all forms of glaucoma is the death of retinal ganglion cells (RGCs), a population of CNS neurons with their soma in the inner retina and axons in the optic nerve. Strategies that delay or halt RGC loss have been recognized as potentially beneficial to preserve vision in glaucoma; however, the succe...
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Excitotoxicity seems to play a critical role in ocular neurodegeneration. Excess-glutamate-mediated retinal ganglion cells death is the principal cause of cell loss. Uncontrolled glutamate in the synapsis has significant implications in the pathogenesis of neurodegenerative disorders. The exploitation of various approaches of controlled release systems enhances the pharmacokinetic and pharmacodynamic activity of drugs. In particular, microparticles are secure, can maintain therapeutic drug conce...
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