α2 Adrenergic Modulation of NMDA Receptor Function as a Major Mechanism of RGC Protection in Experimental Glaucoma and Retinal Excitotoxicity

Dong, Cun-Jian; Guo, Yue; Agey, Peter; Wheeler, Larry A.; Hare, William A.

doi:10.1167/iovs.08-2078

Cited by 133 publications

(109 citation statements)

References 41 publications

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“…The N-methyl-D-aspartate (NMDA) receptors are highly permeable to Ca ++ ions, and an intracellular Ca ++ overload can lead to excitotoxicity and neuronal cell death. Dong and collaborators (2008) has shown that Brimonidine preserves RGCs by blocking NMDA receptors (31) . In addition, Brimonidine has been shown to up-regulate endogenous BDNF expression in RGCs, a potent neuroprotective factor that promotes RGC survival following optic nerve crush injury (32) .…”

Section: Discussionmentioning

confidence: 99%

Brimonidine tartrate effect on retinal spreading depression depends on Müller cells

Oliveira¹,

Rodrigues²,

Alencar³

et al. 2014

Revista Brasileira De Oftalmologia

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Objective: Demonstrate the Brimonidine effect over Retinal Spreading Depression (SD). Brimonidine is an alpha-2-adrenergic receptor agonist, used in the management of glaucoma. Alpha2-agonists have been shown to be neuroprotective in various experimental models, however the molecular and cellular targets leading to these actions are still poorly defined. The SD of neuronal electric activity is a wave of cellular massive sustained depolarization that damages the nervous tissue. Local trauma, pressure, ischemic injuries and other chemical agents as high extracellular potassium concentration or glutamate, can trigger SD, leading to exaggerated focal electrical followed by an electrical silence. Methods: Using chicken retina as model, we performed alpha2-receptor detection by Western Blotting and Immunohistochemistry. After that we obtained electrical signals of SD by microelectrodes on retina in the absence or presence of Brimonidine. For in vivo visualization we observed retina with optical coherence tomography on normal state, with SD passing, and with SD + Brimonidine. Results: Our data demonstrated that: (1) alpha2-adrenergic receptors are present in Müller cells, (2) the treatment with Brimonidine decreases the SD's velocity as well as the voltage of SD waves and (3) OCT revealed that SD creates a hyper reflectance at inner plexiform layer, but on retinal treatment with brimonidine, SD was not visualized. Conclusion: Our study about brimonidine possible pathways of neuroprotection we observed it reduces SD (a neuronal damage wave), identified a new cellular target -the Müller cells, as well as, firstly demonstrated SD on OCT, showing that the inner plexiform layer is the main optically affected layer on SD.Keywords: Retina/drug effects; Adrenergic alpha-2 receptor agonists/therapeutic use; Glaucoma RESUMOObjetivo: Demonstrar o efeito do Tartarato de Brimonidina, um alfa2-agonista usado no manejo do glaucoma, sobre a depressão alastrante (DA) retiniana. Esses agonistas têm demonstrado ser neuroprotetores em vários modelos experimentais, contudo seus alvos celulares e moleculares continuam indefinidos. A DA da atividade elétrica neuronal é uma onda de despolarização celular massiva e sustentada que leva ao dano no tecido nervoso. Trauma local, pressão, isquemia e outros agentes químicos como o aumento do potássio extracelular e o glutamato podem disparar a DA, levando a uma atividade elétrica exagerada seguida de silêncio elétrico. Métodos: Usando a retina de pinto como modelo, realizamos a detecção do alfa2-receptor por Western Blotting e ensaio Imunohistoquímico. Após isso, obtivemos os sinais elétricos da DA através de microeletrodos inseridos na retina durante sua passagem na presença ou ausência de Brimonidina. Para visualização do tecido utilizamos o tomógrafo de coerência optica (OCT), analisando como é a retina no seu estado de repouso, durante a passagem da DA, e a DA + brimonidina. Resultados: Nossos dados demonstraram que: (1) os receptores alfa adrenérgicos presentes na retina são do subtipo-...

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Section: Discussionmentioning

confidence: 99%

Brimonidine tartrate effect on retinal spreading depression depends on Müller cells

Oliveira¹,

Rodrigues²,

Alencar³

et al. 2014

Revista Brasileira De Oftalmologia

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“…Retinal ganglion cells express abundant NMDA receptors [106][107][108][109]. A number of studies demonstrated that ganglion cells are extremely vulnerable to exogenously applied NMDA, which inducesganglion cell degeneration.It has been also shown that NMDA receptor antagonists are neuroprotective in experimental glaucoma models [110][111][112][113][114][115][116][117].…”

Section: A Nmda Receptorsmentioning

confidence: 99%

Excitotoxicity and Glaucoma

Ishikawa¹,

Yoshitomi²,

Izumi³

2014

Ophthalmology - Current Clinical and Research Updates

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“…The positive effect of Brimonidine on RGC survival, that includes a reduction in their soma size in a rat model of o c u l a r h y p e r t e n s i o n , i s b e l i e v e d t o b e m e diated through the attenuation of glutamate toxicity by inhibition of NMDA receptor function (Dong et al, 2008) and/or the upregulation of brain-derived neurotrophic factors (Hernandez et al, 2008). However, in a rat model of pressure-induced retinal ischemia, it was suggested that Brimonidine's neuroprotective effect is mediated via the inhibition of the apoptotic cascade, possibly through the induction of anti-apoptotic genes such as bcl-2 and bcl-x, as well as extracellular-signal regulated kinases (ERKs) and phosphatidylinositol-30 kinase/ protein kinase Akt pathways (Lai et al, 2002).While Brimonidine's effect on RGCs in isolated rat retinas, as well as in vivo in rat and rabbit glaucoma models was also shown to be mediated through the reduction of a2-adrenoceptor mediated reduction of intracellular cAMP (Dong et al, 2008). A clinical trial assessing the non-IOP-related effects of Brimonidine, demonstrated reduced visual field deterioration in comparison to 360° laser trabeculoplasty (Gandolfi et al, 2003) .…”

Section: Compounds With Multiple/novel Mechanisms Of Actionmentioning

confidence: 99%

“…As a result, energy compromised neurons cannot maintain ionic homeostasis and become depolarized. Modulation of the NMDA receptor has been constituted a major area of research in glaucoma neuroprotection (Dong et al, 2008;Guo et al, 2006). In vivo and in vitro studies have suggested that blocking both the NMDA and the non-NMDA receptors simultaneously offers optimal protection against ischemic neurodegeneration (Mosinger et al, 1991).…”

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confidence: 99%