Inhibition of nitric-oxide synthase 2 by aminoguanidine provides neuroprotection of retinal ganglion cells in a rat model of chronic glaucoma

Neufeld, Arthur H.; Sawada, Akira; Becker, Bernard

doi:10.1073/pnas.96.17.9944

Cited by 335 publications

(229 citation statements)

References 21 publications

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“…Retinal ganglion cells were identified in rats by retrograde labeling with FluoroGold (Fluorochrome, Inc.) bilaterally injected into the superior collicular brachium (46). FG (5%, 2.4 L/ injection) diluted in saline was microinjected bilaterally into the superior colliculi of anesthetized rats immobilized in a stereotaxic apparatus.…”

Section: Retrograde Labeling Of Retinal Ganglion Cellsmentioning

confidence: 99%

Single-cell imaging of retinal ganglion cell apoptosis with a cell-penetrating, activatable peptide probe in an in vivo glaucoma model

Barnett

Zhang

Maxwell

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

126

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Molecular imaging probes have potential for in vivo identification of apoptosis and other intracellular processes. TcapQ, a cell-penetrating, near-infrared fluorescent peptide probe designed to be optically silent through intramolecular fluorescence quenching and activated by effector caspases, has been previously described and validated in vitro. Herein, using NMDA-induced apoptosis of retinal ganglion cells (RGCs), representing an in vivo rat model of glaucoma, we assessed the ability of TcapQ to image single-cell apoptosis through effector caspase activity. Following intravitreal injection, intracellular TcapQ activation occurred specifically in RGCs, identified individual apoptotic cells, showed a clear dose-response relationship with NMDA, and colocalized with TUNEL labeling in the retina. There was a significant diminution of probe activation following pretreatment with a specific inhibitor of caspase-3. Stereospecificity was also exhibited by the lack of intracellular fluorescence upon administration of the noncleavable isomer, d TcapQ. TcapQ has potential utility in detecting and monitoring single-cell apoptosis in glaucoma in vivo.

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Section: Retrograde Labeling Of Retinal Ganglion Cellsmentioning

confidence: 99%

Single-cell imaging of retinal ganglion cell apoptosis with a cell-penetrating, activatable peptide probe in an in vivo glaucoma model

Barnett

Zhang

Maxwell

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

126

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“…29, 32, and 33). Recent studies have shown, for example, that treatment with a glutamate antagonist (34) or a nitric oxide synthase inhibitor (35) attenuates RGC death in a rat model of increased IOP. The present finding is potentially of great interest clinically because (i) it shows that neuroprotection can be achieved even when the pressure remains high [indeed, even a pressure reduced to normal is not necessarily safe for patients with glaucoma, in whom the remaining neurons are more vulnerable than normal ones (36)]; and (ii) it is based on a strategy that harnesses and augments the tissue's own defense machinery.…”

Section: Discussionmentioning

confidence: 99%

Vaccination for protection of retinal ganglion cells against death from glutamate cytotoxicity and ocular hypertension: Implications for glaucoma

Schori

Kipnis

Yoles

et al. 2001

Proc. Natl. Acad. Sci. U.S.A.

275

181

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Our group recently demonstrated that autoimmune T cells directed against central nervous system-associated myelin antigens protect neurons from secondary degeneration. We further showed that the synthetic peptide copolymer 1 (Cop-1), known to suppress experimental autoimmune encephalomyelitis, can be safely substituted for the natural myelin antigen in both passive and active immunization for neuroprotection of the injured optic nerve. Here we attempted to determine whether similar immunizations are protective from retinal ganglion cell loss resulting from a direct biochemical insult caused, for example, by glutamate (a major mediator of degeneration in acute and chronic optic nerve insults) and in a rat model of ocular hypertension. Passive immunization with T cells reactive to myelin basic protein or active immunization with myelin oligodendrocyte glycoprotein-derived peptide, although neuroprotective after optic nerve injury, was ineffective against glutamate toxicity in mice and rats. In contrast, the number of surviving retinal ganglion cells per square millimeter in glutamate-injected retinas was significantly larger in mice immunized 10 days previously with Cop-1 emulsified in complete Freund's adjuvant than in mice injected with PBS in the same adjuvant (2,133 ؎ 270 and 1,329 ؎ 121, respectively, mean ؎ SEM; P < 0.02). A similar pattern was observed when mice were immunized on the day of glutamate injection (1,777 ؎ 101 compared with 1,414 ؎ 36; P < 0.05), but not when they were immunized 48 h later. These findings suggest that protection from glutamate toxicity requires reinforcement of the immune system by antigens that are different from those associated with myelin. The use of Cop-1 apparently circumvents this antigen specificity barrier. In the rat ocular hypertension model, which simulates glaucoma, immunization with Cop-1 significantly reduced the retinal ganglion cell loss from 27.8% ؎ 6.8% to 4.3% ؎ 1.6%, without affecting the intraocular pressure. This study may point the way to a therapy for glaucoma, a neurodegenerative disease of the optic nerve often associated with increased intraocular pressure, as well as for acute and chronic degenerative disorders in which glutamate is a prominent participant.

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“…This highly potent secondary oxidant has been implicated in glaucomatous injury (Neufeld et al, 1999).…”

Section: Interplay Of Tnf-α Signaling With Other Cellular Events Assomentioning

confidence: 99%

TNF-α signaling in glaucomatous neurodegeneration

Tezel

2008

Progress in Brain Research

237

190

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Growing evidence supports the role of TNF-α as a mediator of neurodegeneration in glaucoma. Glial production of TNF-α is increased and its death receptor is up-regulated on retinal ganglion cells (RGCs) and optic nerve axons in glaucomatous eyes. This multifunctional cytokine can induce RGC death through receptor-mediated caspase activation, mitochondrial dysfunction, and oxidative stress. Opposing these cell-death promoting signals, binding of TNF receptors can also trigger the activation of survival signals. A critical balance between a variety of intracellular signaling pathways determines the predominant in vivo bioactivity of TNF-α as best exemplified by differential responses of RGCs and glia. In addition to the direct neurotoxicity of TNF-α to RGCs and their axons, potential interplay of TNF-α signaling with other cellular events associated with glaucomatous neurodegeneration may also contribute to secondary neurodegenerative injury. This review focuses on the present evidence supporting the involvement of TNF-α signaling in glaucomatous neurodegeneration and possible treatment targets to provide neuroprotection.

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Inhibition of nitric-oxide synthase 2 by aminoguanidine provides neuroprotection of retinal ganglion cells in a rat model of chronic glaucoma

Cited by 335 publications

References 21 publications

Single-cell imaging of retinal ganglion cell apoptosis with a cell-penetrating, activatable peptide probe in an in vivo glaucoma model

Single-cell imaging of retinal ganglion cell apoptosis with a cell-penetrating, activatable peptide probe in an in vivo glaucoma model

Vaccination for protection of retinal ganglion cells against death from glutamate cytotoxicity and ocular hypertension: Implications for glaucoma

TNF-α signaling in glaucomatous neurodegeneration

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