Nω-Nitro-l-arginine methyl ester protects retinal neurons against N-methyl-d-aspartate-induced neurotoxicity in vivo

Morizane, Chikako; Adachi, Kei; Furutani, I.; Fujita, Yasuhiko; Akaike, Akinori; Kashii, Satoshi; Honda, Yoshio

doi:10.1016/s0014-2999(97)83026-9

Cited by 56 publications

(40 citation statements)

References 19 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…23 These results establish a causal role of peroxynitrite in mediating retinal neurotoxicity and lend further support to previous reports showing protective effects of blocking peroxynitrite indirectly using the NOS inhibitor L-NAME, iNOS inhibitor aminoguanidine, or the superoxides and hydroxyl radicals scavenger TEMPOL in NMDA or ischemia/reperfusion model. 1,2,24,25 The neuroprotective effects of FeTPPs were screened after 1 day of NMDA injection, a time point at which, RGC death will peak then plateau afterward. 1,26 Indeed, peroxynitrite decomposition catalysts, such as FeTPPs and FP15 have been proven effective in reducing peroxynitrite-mediated insults in models of ischemic retinopathy, diabetic retinopathy, and neuropathy.…”

Section: Figure 5 Fetpps Blocked Activation Of P38 Mapk Apoptosis Pamentioning

confidence: 99%

Neurovascular Protective Effect of FeTPPs in N-Methyl-D-Aspartate Model

Al‐Gayyar

Abdelsaid

Matragoon

et al. 2010

The American Journal of Pathology

View full text Add to dashboard Cite

We have previously shown a causal role of peroxynitrite in mediating retinal ganglion cell (RGC) death in diabetic and neurotoxicity models. In the present study, the role of peroxynitrite in altering the antioxidant and antiapoptotic thioredoxin (Trx) system will be investigated as well as the subsequent effects on glial activation and capillary degeneration. Excitotoxicity of the retina was induced by intravitreal injection of N-methyl-Daspartate (NMDA) in rats, which also received the peroxynitrite decomposition catalyst FeTPPs. Retinal ganglion cell (RGC) death plays a critical role in the pathogenesis of many retinal neurodegenerative disorders, including glaucoma, diabetic retinopathy, traumatic optic neuropathy, uveitis, and retinal ischemia. [1][2][3][4][5] Understanding the molecular mechanism of neuronal cell death in such retinal diseases is of great clinical important for devising new treatments. In response to traumatic or ischemic injury, excessive activation of glutamate receptors has been implicated in the RGC death process. 6 Therefore, administration of N-methyl-D-aspartate (NMDA) to rodent eyes is a reliable model to study RGC death. Excessive NMDA receptor stimulation leads to excessive Ca 2ϩ influx, 7 which in turn triggers formation of nitric oxide 8 and accumulation of superoxides and their combination product peroxynitrite, causing lipid peroxidation, DNA damage and the eventual cell death. 9 Although increases in reactive oxygen species (ROS) and peroxynitrite have been implicated in mediating RGC death, 1,6 the molecular mechanisms by which peroxynitrite causes RGC death are not fully elucidated.Protection from ROS is mediated by superoxide dismutase, glutathione, and thioredoxin (Trx) systems. 10,11

show abstract

Section: Figure 5 Fetpps Blocked Activation Of P38 Mapk Apoptosis Pamentioning

confidence: 99%

Neurovascular Protective Effect of FeTPPs in N-Methyl-D-Aspartate Model

Al‐Gayyar

Abdelsaid

Matragoon

et al. 2010

The American Journal of Pathology

View full text Add to dashboard Cite

show abstract

“…Intravitreal injections were carried out as previously described (31). Fasudil was dissolved in intraocular irrigating solution (OpeguardMA, Senju Pharmaceutical, Osaka, Japan).…”

Section: Methodsmentioning

confidence: 99%

Rho Kinase Inhibition by Fasudil Ameliorates Diabetes-Induced Microvascular Damage

et al. 2009

View full text Add to dashboard Cite

OBJECTIVE-Leukocyte adhesion in retinal microvasuculature substantially contributes to diabetic retinopathy. Involvement of the Rho/Rho kinase (ROCK) pathway in diabetic microvasculopathy and therapeutic potential of fasudil, a selective ROCK inhibitor, are investigated. RESEARCH DESIGN AND METHODS-Localization ofRhoA/ROCK and Rho activity were examined in retinal tissues of rats. Impact of intravitreal fasudil administration on retinal endothelial nitric oxide synthase (eNOS) and myosin phosphatase target protein (MYPT)-1 phosphorylation, intercellular adhesion molecule-1 (ICAM-1) expression, leukocyte adhesion, and endothelial damage in rat eyes were investigated. Adhesion of neutrophils from diabetic retinopathy patients or nondiabetic control subjects to cultured microvascular endothelial cells was quantified. The potential of fasudil for endothelial protection was investigated by measuring the number of adherent neutrophils and terminal transferase-mediated dUTP nick-end labeling-positive endothelial cells.RESULTS-RhoA and ROCK colocalized predominantly in retinal microvessels. Significant Rho activation was observed in retinas of diabetic rats. Intravitreal fasudil significantly increased eNOS phosphorylation, whereas it reduced MYPT-1 phosphorylation, ICAM-1 expression, leukocyte adhesion, and the number of damaged endothelium in retinas of diabetic rats. Neutrophils from diabetic retinopathy patients showed significantly higher adhesion to cultured endothelium and caused endothelial apoptosis, which was significantly reduced by fasudil. Blockade of the Fas-FasL interaction prevented endothelial apoptosis. The protective effect of fasudil on endothelial apoptosis was significantly reversed by N-nitro-L-arginine methyl ester, a NOS inhibitor, whereas neutrophil adhesion remained unaffected. CONCLUSIONS-The

show abstract

“…The excitotoxic RGC injury model was prepared in a manner similar to that previously described [22,23]. After anaesthetising the rats with isoflurane (2.5 L/min isoflurane in 2.5 L/min oxygen), instilling topical 0.4% benoxinate drops in both eyes and applying a sterile loop around the globes, a single dose of 5 μl of 4 mM NMDA (20 nmol, source- Sigma Aldrich, USA) was injected slowly over 30 seconds into the vitreous space of the left eye using a microsyringe fitted with a 30-gauge needle.…”

Section: Methodsmentioning

confidence: 99%

Wallerian-like axonal degeneration in the optic nerve after excitotoxic retinal insult: an ultrastructural study

et al. 2010

View full text Add to dashboard Cite

BackgroundExcitotoxicity is involved in the pathogenesis of a number neurodegenerative diseases, and axonopathy is an early feature in several of these disorders. In models of excitotoxicity-associated neurological disease, an excitotoxin delivered to the central nervous system (CNS), could trigger neuronal death not only in the somatodendritic region, but also in the axonal region, via oligodendrocyte N-methyl-D-aspartate (NMDA) receptors. The retina and optic nerve, as approachable regions of the brain, provide a unique anatomical substrate to investigate the "downstream" effect of isolated excitotoxic perikaryal injury on central nervous system (CNS) axons, potentially providing information about the pathogenesis of the axonopathy in clinical neurological disorders.Herein, we provide ultrastructural information about the retinal ganglion cell (RGC) somata and their axons, both unmyelinated and myelinated, after NMDA-induced retinal injury. Male Sprague-Dawley rats were killed at 0 h, 24 h, 72 h and 7 days after injecting 20 nM NMDA into the vitreous chamber of the left eye (n = 8 in each group). Saline-injected right eyes served as controls. After perfusion fixation, dissection, resin-embedding and staining, ultrathin sections of eyes and proximal (intraorbital) and distal (intracranial) optic nerve segments were evaluated by transmission electron tomography (TEM).ResultsTEM demonstrated features of necrosis in RGCs: mitochondrial and endoplasmic reticulum swelling, disintegration of polyribosomes, rupture of membranous organelle and formation of myelin bodies. Ultrastructural damage in the optic nerve mimicked the changes of Wallerian degeneration; early nodal/paranodal disturbances were followed by the appearance of three major morphological variants: dark degeneration, watery degeneration and demyelination.ConclusionNMDA-induced excitotoxic retinal injury causes mainly necrotic RGC somal death with Wallerian-like degeneration of the optic nerve. Since axonal degeneration associated with perikaryal excitotoxic injury is an active, regulated process, it may be amenable to therapeutic intervention.

show abstract

Nω-Nitro-l-arginine methyl ester protects retinal neurons against N-methyl-d-aspartate-induced neurotoxicity in vivo

Cited by 56 publications

References 19 publications

Neurovascular Protective Effect of FeTPPs in N-Methyl-D-Aspartate Model

Neurovascular Protective Effect of FeTPPs in N-Methyl-D-Aspartate Model

Rho Kinase Inhibition by Fasudil Ameliorates Diabetes-Induced Microvascular Damage

Wallerian-like axonal degeneration in the optic nerve after excitotoxic retinal insult: an ultrastructural study

Contact Info

Product

Resources

About