Neurochemical Evidence to Implicate Elevated Glutamate in the Mechanisms of High Intraocular Pressure (IOP)-induced Retinal Ganglion Cell Death in Rat

Nucci, Carlo Alberto; Tartaglione, R.; Rombolà, Laura; Morrone, Luigi Antonio; Fazzi, Elisa; Bagetta, Giacinto

doi:10.1016/j.neuro.2005.06.002

Cited by 134 publications

(93 citation statements)

References 19 publications

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“…Oxidative neuronal injury in glaucoma may also be associated with excitotoxic amino acids, including glutamate, which are known to induce ROS generation; and oxidative stress is a leading mechanism of glutamate neurotoxicity (Atlante et al, 2001). In addition, retinal glutamate damage has been shown to be mediated in part through nitric oxide, a highly reactive oxidant (Nucci et al, 2005). Free radical scavenging when combined with trophic factors has resulted in increased survival of RGCs in ocular hypertensive rat eyes (Ko et al, 2000).…”

Section: Proposed Pathogenic Mechanisms Of Glaucomatous Neurodegeneramentioning

confidence: 99%

Oxidative stress in glaucomatous neurodegeneration: Mechanisms and consequences

Tezel

2006

Progress in Retinal and Eye Research

612

449

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Reactive oxygen species (ROS) are generated as by-products of cellular metabolism, primarily in the mitochondria. Although ROS are essential participants in cell signaling and regulation, when their cellular production overwhelms the intrinsic antioxidant capacity, damage to cellular macromolecules such as DNA, proteins, and lipids ensues. Such a state of "oxidative stress" is thought to contribute to the pathogenesis of a number of neurodegenerative diseases. Growing evidence supports the involvement of oxidative stress as a common component of glaucomatous neurodegeneration in different subcellular compartments of retinal ganglion cells (RGCs). Besides the evidence of direct cytotoxic consequences leading to RGC death, it also seems highly possible that ROS are involved in signaling RGC death by acting as a second messenger and/or modulating protein function by redox modifications of downstream effectors through enzymatic oxidation of specific amino acid residues. Different studies provide cumulating evidence, which supports the association of ROS with different aspects of the neurodegenerative process. Oxidative protein modifications during glaucomatous neurodegeneration increase neuronal susceptibility to damage and also lead to glial dysfunction. Oxidative stress-induced dysfunction of glial cells may contribute to spreading neuronal damage by secondary degeneration. Oxidative stress also promotes the accumulation of advanced glycation end products in glaucomatous tissues. It is also evident that oxidative stress takes part in the activation of immune response during glaucomatous neurodegeneration, as ROS stimulate the antigen presenting ability of glial cells and also function as co-stimulatory molecules during antigen presentation. By discussing current evidence, this review provides a broad perspective on cellular mechanisms and potential consequences of oxidative stress in glaucoma.

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Section: Proposed Pathogenic Mechanisms Of Glaucomatous Neurodegeneramentioning

confidence: 99%

Oxidative stress in glaucomatous neurodegeneration: Mechanisms and consequences

Tezel

2006

Progress in Retinal and Eye Research

612

449

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“…Glutamate exerts its action through ionotropic [amino-methyl-propionic-acid (AMPA), N-methyl-daspartate (NMDA) and kainate GluRs] and metabotropic receptors [89,90]. It is also a potent neurotoxin involved in RGC death in hypoxic-ischemic conditions [91,92] where increased accumulation of glutamate occurs in the extracellular spaces in the retinal tissue. Glutamate has been shown to affect the ganglion cell layer and also cause necrosis of cells in the inner retina [93].…”

Section: Hypoxia and Glutamatementioning

confidence: 99%

Cellular and Molecular Mechanisms of Retinal Ganglion Cell Death in Hypoxic-Ischemic Injuries

Kaur¹,

Rathnasamy²,

Foulds³

et al. 2015

J Neurol Exp Neurosci

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Loss of retinal ganglion cells (RGCs) occurs in retinal degenerative diseases, such as glaucoma, age-related macular degeneration, diabetic retinopathy, central retinal artery occlusion and ischemic central retinal vein thrombosis in adults and in retinopathy of prematurity in infants. A critical role of hypoxia, which underlies most of the above disorders, has been reported in causing RGC death. Disruption of blood-retinal barrier (BRB) occurs due to increased production of vascular endothelial growth factor and nitric oxide in response to hypoxia resulting in extravasation of serum derived substances and retinal edema and this may be one of important factors mediating RGC death. Activation of microglial cells in response to hypoxia and subsequent increased release of proinflammatory cytokines by them such as tumor-necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) target the TNF-receptor 1 and IL-receptor 1 on RGCs. Excess release of glutamate in retinal tissue under hypoxia activates the ionotropic glutamate receptors causing excitotoxicity through increased influx of calcium into the RGCs. Increased production of TNF-α, IL-1β and enhanced intracellular calcium results in RGC death through activating several pathways such as caspase signaling, mitochondrial dysfunction and oxidative stress. In our investigations, melatonin, an antioxidant, was shown to reduce RGC death in the adult and neonatal hypoxic retina, through suppression of TNF-α, IL-1β and glutamate levels as well as oxidative stress. Moreover, the function and structure of BRB was well preserved in these animals along with reduction in retinal edema. In view of our observations, we suggest that melatonin could be considered as a therapeutic agent to reduce RGC death in various retinal pathologies, in addition to other potential drugs/molecules of therapeutic interest that could render protection to RGCs. However, future in-depth research on the effects of melatonin on the retina under hypoxic conditions needs to be undertaken to explore its full potential in preventing/ameliorating RGC death. Factors Mediating RGC DeathSeveral factors induced or upregulated by hypoxia may be involved in causing RGC death. These factors include, among others, disruption of the blood-retinal barrier, activation of microglial cells and the accompanying enhanced release of inflammatory cytokines and excess release and accumulation of glutamate in the retinal tissues. Hypoxia and the blood-retinal barrierThe BRB regulates the passage of molecules from blood into the retina [11,12]. It consists of an inner BRB formed by the tight junctions (TJ) between capillary endothelial cells and an outer barrier formed by TJ between retinal pigment epithelial cells [12][13][14][15][16]. The TJ are made up of transmembrane proteins such as occludin, claudin-5 and cytoplasmic proteins such as zona occludens (ZO)-1 that are structurally and functionally important for maintaining the integrity of the BRB. The proper functioning of the inner BRB also requires the collective co...

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“…Lowering IOP slows down the progression of glaucomatous damage; however, clinical evidence suggests that glaucoma patients vary greatly in their susceptibility to elevated IOP. 28 -30 Several factors, including oxidative stress, 31 mitochondrial dysfunction, 32 and glutamate neurotoxicity 33,34 are proposed to work concomitantly in the pathogenesis of the disease and in regulating RGC susceptibility to glaucomatous damage. 35,36 Given possible involvement of NGB in these cellular functions, we hypothesized that NGB plays a role in glaucoma and may represent a novel target for treatment of the disease.…”

mentioning

confidence: 99%

Neuroglobin Is an Endogenous Neuroprotectant for Retinal Ganglion Cells against Glaucomatous Damage

Wei

Cho

et al. 2011

The American Journal of Pathology

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Neuroglobin (NGB), a newly discovered member of the globin superfamily, may regulate neuronal survival under hypoxia or oxidative stress. Although NGB is greatly expressed in retinal neurons, the biological functions of NGB in retinal diseases remain largely unknown. We investigated the role of NGB in an experimental model of glaucoma, a neurodegenerative disorder that usually involves elevation of intraocular pressure (IOP). Elevated IOP is thought to induce oxidative stress in retinal ganglion cells (RGCs), thereby causing RGC death and, eventually, blindness. We found that NGB plays a critical role in increasing RGC resistance to ocular hypertension and glaucomatous damage. Neuroglobin (NGB) is a novel member of the globin superfamily that is distantly related to hemoglobin and myoglobin. 1 A highly conserved protein in evolution, human and mouse Ngb, both comprised of 151 amino acids, are 94% identical. 2,3 In mammals, expression of NGB is found in the brain, retina, and other nerve tissues, predominantly in neurons but absent from glial cells. 4 -7 Distribution of NGB protein in the normal human retina is very similar to what has been described in mice: NGB is detected primarily in the plexiform layers and photoreceptor inner segments, which are rich in mitochondria and synapses and consume high amounts of oxygen. 8,9 NGB has been shown to act as an endogenous neuroprotective molecule that enhances neuronal survival under hypoxic-ischemic insults in the brain 10 -12 ; however, its physiological functions and molecular mode of actions are not fully understood. Of note, NGB is present at a 100-fold greater concentration in the retina than in the brain, 8,[13][14][15] suggesting that the retina may be its most important site of function; however, among the many unknown roles of NGB, functional significance of NGB expression in the retina has been largely unexplored.

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Neurochemical Evidence to Implicate Elevated Glutamate in the Mechanisms of High Intraocular Pressure (IOP)-induced Retinal Ganglion Cell Death in Rat

Cited by 134 publications

References 19 publications

Oxidative stress in glaucomatous neurodegeneration: Mechanisms and consequences

Oxidative stress in glaucomatous neurodegeneration: Mechanisms and consequences

Cellular and Molecular Mechanisms of Retinal Ganglion Cell Death in Hypoxic-Ischemic Injuries

Neuroglobin Is an Endogenous Neuroprotectant for Retinal Ganglion Cells against Glaucomatous Damage

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