A Proposed Role for Excitotoxicity in Glaucoma

Dreyer, Evan B.

doi:10.1097/00061198-199802000-00012

Cited by 111 publications

(78 citation statements)

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“…Retinal ganglion cells are extremely sensitive to the effects of both glutamate and its analog N-methyl-D-aspartate (NMDA), both of which produce a dosedependent cell loss in vivo and in vitro. In addition, glutamate toxicity has been implicated in the pathophysiology of glaucoma (Dreyer, 1998). Activation of Ca 2ϩ -permeable NMDA receptors and the subsequent neuronal Ca 2ϩ overloading have been shown to mediate glutamate-induced neuron death (Choi, 1994).…”

Section: Introductionmentioning

confidence: 99%

A Novel Calpain Inhibitor, ((1S)-1-((((1S)-1-Benzyl-3-cyclopropylamino-2,3-di-oxopropyl)amino)carbonyl)-3-methylbutyl)carbamic Acid 5-Methoxy-3-oxapentyl Ester (SNJ-1945), Reduces Murine Retinal Cell Death In Vitro and In Vivo

Shimazawa¹,

Suemori²,

Inokuchi³

et al. 2009

J Pharmacol Exp Ther

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We examined whether ((1S)-1-((((1S)-1-benzyl-3-cyclopropylamino-2,3-di-oxopropyl)amino)carbonyl)-3-methylbutyl)carbamic acid 5-methoxy-3-oxapentyl ester (SNJ-1945), a new orally available calpain inhibitor, might reduce retinal cell death in vivo and/or in vitro. Retinal cell damage was induced in vivo in mice by intravitreal injection of N-methyl-D-aspartate (NMDA), and SNJ-1945 was intraperitoneally or orally administered twice. NMDA-induced calpain activity (measured as the cleaved products of ␣-spectrin) and its substrate, p35 (a neuron-specific activator for cyclin-dependent kinase 5), in the retina were examined by immunoblotting. In RGC-5 (a rat retinal ganglion cell line) cell culture, cell damage was induced by a 4-h oxygenglucose deprivation (OGD) treatment followed by an 18-h reoxygenation period. In mouse retinas, SNJ-1945 (30 or 100 mg/kg i.p., 100 or 200 mg/kg p.o.) significantly inhibited the cell loss in the ganglion cell layer (GCL) and the thinning of the inner plexiform layer induced by NMDA. Furthermore, the number of positive cells for terminal deoxynucleotidyl transferase dUTP nick-end labeling was significantly reduced in the GCL and the inner nuclear layer of retinas treated with SNJ-1945 compared with vehicle-treated retinas 24 h after NMDA injection. Levels of cleaved ␣-spectrin products increased and p35 decreased 6 h after NMDA injection or later, and their effects were attenuated by SNJ-1945. In vitro, SNJ-1945 (10 and 100 M) inhibited the OGD stress-induced reduction in cell viability. In conclusion, SNJ-1945 may afford valuable neuroprotection against retinal diseases, because it was effective against retinal damage both in vitro and in vivo. Our results also indicate that calpain activation and subsequent p35 degradation may be involved in the mechanisms underlying retinal cell death.Retinal ganglion cell (RGC) death is a common feature of many ophthalmic disorders, including glaucoma, optic neuropathies, and various retinovascular diseases (diabetic retinopathy and retinal vein occlusions). Retinal ganglion cells are extremely sensitive to the effects of both glutamate and its analog N-methyl-D-aspartate (NMDA), both of which produce a dosedependent cell loss in vivo and in vitro. In addition, glutamate toxicity has been implicated in the pathophysiology of glaucoma (Dreyer, 1998). Activation of Ca 2ϩ -permeable NMDA receptors and the subsequent neuronal Ca 2ϩ overloading have been shown to mediate glutamate-induced neuron death (Choi, 1994). Induction of the Ca 2ϩ -activated neutral cysteine protease -calpain by micromolar concentrations of Ca 2ϩ occurs early in excitotoxic neuron death (Siman et al., 1989;Faddis et al., 1997). Similar to the caspases, -calpain cleaves a variety of cytoskeletal proteins, enzymes, and transcription factors and could also interfere with the proteolytic activity of the caspases (Croall and DeMartino, 1991).

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Section: Introductionmentioning

confidence: 99%

A Novel Calpain Inhibitor, ((1S)-1-((((1S)-1-Benzyl-3-cyclopropylamino-2,3-di-oxopropyl)amino)carbonyl)-3-methylbutyl)carbamic Acid 5-Methoxy-3-oxapentyl Ester (SNJ-1945), Reduces Murine Retinal Cell Death In Vitro and In Vivo

Shimazawa¹,

Suemori²,

Inokuchi³

et al. 2009

J Pharmacol Exp Ther

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show abstract

“…In addition, RGC are exquisitely sensitive to the effects of both glutamate and its analog Nmethyl-D-aspartate (NMDA), which produces a dose-dependent cell loss both in vivo and in vitro, and indeed glutamate toxicity has been implicated in the pathophysiology of glaucoma (Dreyer, 1998). NMDA-induced calcium entry and ROS production are well recognized to be mediators of ischemic neuronal damage, and activation of NMDA receptors reportedly generates free radicals and reduces antioxidant ability in the rat hippocampus (Ueda et al, 2007).…”

mentioning

confidence: 99%

Edaravone, a Free Radical Scavenger, Protects against Retinal Damage in Vitro and in Vivo

Inokuchi¹,

Imai²,

Nakajima³

et al. 2009

J Pharmacol Exp Ther

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Edaravone (3-methyl-1-phenyl-2-pyrazolin-5-one), a free radical scavenger, is used for the treatment of acute cerebral infarction. In this study, we investigated whether edaravone is neuroprotective against retinal damage. In vitro, we used a radical-scavenging capacity assay using reactive oxygen species-sensitive probes to investigate the effects of edaravone on H 2 O 2 , superoxide anion (O 2 . ), and hydroxyl radical ( ⅐ OH) production in a rat retinal ganglion cell line (RGC-5). The effect of edaravone on oxygen-glucose deprivation (OGD)-induced RGC-5 damage was evaluated using a 2-(2-methoxy-4-nitrophenyl)-3-(4-nitrophenyl)-5-(2,4-disulfophenyl)-2H-tetrazolium, monosodium salt assay of cell viability. Edaravone (3-methyl-1-phenyl-2-pyrazolin-5-one) significantly decreased radical generation and reduced the cell death induced by OGD stress. In vivo, retinal damage was induced by intravitreous injection of N-methyl-D-aspartate (NMDA; 5 nmol) and was evaluated by examining ganglion cell layer cell loss, terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL) staining, and the expressions of two oxidant-stress markers [4-hydroxy-2-nonenal (4-HNE) and 8-hydroxy-2-deoxyguanosine (8-OHdG)]. In addition, activations of mitogenactivated protein kinases (MAPKs) [extracellular signalregulated protein kinases (ERK), c-Jun NH 2 -terminal kinases (JNK), and p38 MAPK], as downstream signal pathways after NMDA receptor activation, were measured using immunoblotting and immunostaining. Edaravone at 5 and 50 nmol intravitreous injection or at 1 and 3 mg/kg i.v. significantly protected against NMDA-induced retinal cell death. At 50 nmol intravitreous injection, it 1) decreased the retinal expressions of TUNELpositive cells, 4-HNE, and 8-OHdG and 2) reduced the retinal expressions of NMDA-induced phosphorylated JNK and phosphorylated p38 but not that of phosphorylated ERK. These findings suggest that oxidative stress plays a pivotal role in retinal damage and that edaravone may be a candidate for the effective treatment of retinal diseases.

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“…Excessive amounts of glutamate, which causes excitotoxic cell death of RGCs, have been detected in the vitreous of glaucoma patients [102]. The amino acid glutamate is an essential neurotransmitter in the central nervous system and the retina.…”

Section: Glutamate Antagonistsmentioning

confidence: 99%

Diabetes Mellitus and Retinal Vein Occlusion as Risk Factors for Open Angle Glaucoma and Neuroprotective Therapies for Retinal Ganglion Cell Neuropathy

Bikbova¹,

Oshitari²,

Yamamoto³

2011

J Clin Exp Ophthalmol

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of glaucoma (NTG), and the prevalence of NTG is 3.6% in patients >40-years-of-age in Japan [10]. The average intraocular pressure (IOP) in patients with POAG is 15.4 ± 2.8 mmHg, which is significantly higher than that of normal subjects (14.5 ± 2.5 mmHg) [1][2][3][4][5][6][7][8][9][10] even though the average difference in the IOP is only 0.9 mmHg. Thus, a reduction of the IOP the standard therapy for glaucoma may not be sufficient for the complete management of the patients with glaucoma in Japan. Other therapeutic modalities, such as neuroprotection, should be considered for a complete therapeutic regimen for glaucoma patients.RGC death and axonal degeneration are most likely involved in the progression of DR, RVO, and glaucoma. Many neuroprotective therapies that prevent RGC death and axonal degeneration have been and are being investigated, and some of these neuroprotective factors may be used clinically in the near future. To establish neuroprotective therapies for DR, RVO and glaucoma, a determination of the exact mechanism that leads to a progression of RGC neuropathy to death and axonal degeneration is required [11]. However, the pathogenesis of the onset and progression of RGC neuropathy has still not been definitively determined. Identification of the risk factors for the onset and the progression of disease would help in determining the Abstract Glaucoma, diabetic retinopathy (DR), and retinal vein occlusion (RVO) are major diseases that can lead to blindness and affect mainly the elderly population worldwide. The results of recent investigations have demonstrated that the death of retinal ganglion cells (RGCs) and their axons is the common pathological change in these three disease processes. The exact mechanism that is responsible for the onset and progression of RGC death and axonal degeneration in patients with glaucoma, DR and RVO has not been definitively determined. Thus, identifying the risk factors for the onset and the progression of RGC neuropathy can help in deciding not only the specific treatments but also whether the treatments should be initiated, withheld, or augmented in individuals with glaucoma, DR, and RVO. This review describes the major risk factors for the onset of glaucoma, and the factors associated with the progression of glaucoma that have been obtained from large population-based prevalence and incidence studies. In addition, the potential risk factors for glaucoma, diabetes mellitus, and RVO are discussed in terms of the results obtained by both clinical and laboratory studies. This review introduces potential neuroprotective therapies for damaged RGC in eyes with RGC neuropathy, and the factors that should be considered for a complete therapy for the RGC neuropathy involved in glaucoma, DR and RVO. Neuroprotective therapies combined with a reduction of the IOP should be considered for the complete management of RGC neuropathy involved in glaucoma,

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A Proposed Role for Excitotoxicity in Glaucoma

Cited by 111 publications

References 0 publications

A Novel Calpain Inhibitor, ((1S)-1-((((1S)-1-Benzyl-3-cyclopropylamino-2,3-di-oxopropyl)amino)carbonyl)-3-methylbutyl)carbamic Acid 5-Methoxy-3-oxapentyl Ester (SNJ-1945), Reduces Murine Retinal Cell Death In Vitro and In Vivo

A Novel Calpain Inhibitor, ((1S)-1-((((1S)-1-Benzyl-3-cyclopropylamino-2,3-di-oxopropyl)amino)carbonyl)-3-methylbutyl)carbamic Acid 5-Methoxy-3-oxapentyl Ester (SNJ-1945), Reduces Murine Retinal Cell Death In Vitro and In Vivo

Edaravone, a Free Radical Scavenger, Protects against Retinal Damage in Vitro and in Vivo

Diabetes Mellitus and Retinal Vein Occlusion as Risk Factors for Open Angle Glaucoma and Neuroprotective Therapies for Retinal Ganglion Cell Neuropathy

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