N-methyl-D-aspartate-induced neurotoxicity in the adult rat retina

Siliprandi, Renata; Canella, R.; Carmignoto, Giorgio; Schiavo, Nicola; Zanellato, Anna Maria Cecilia; Zanoni, R.; Vantini, G.

doi:10.1017/s0952523800005666

Cited by 259 publications

(147 citation statements)

References 38 publications

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“…A single intravitreal injection of 20 nM of NMDA killed 70% of retinal ganglion cells in the adult rat retina. 15 These findings support the hypothesis that increased glutamate synthesis or decreased glutamate clearance results in excitotoxic damage to ganglion cells and contributes to the pathophysiology of glaucoma. However, if this is true, elevated glutamate levels should be detected in both the eyes of humans with glaucoma and animal models.…”

supporting

confidence: 78%

Glutamate excitotoxicity in glaucoma: truth or fiction?

Lotery

2005

Eye

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supporting

confidence: 78%

Glutamate excitotoxicity in glaucoma: truth or fiction?

Lotery

2005

Eye

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“…In the adult rat, this dose of NMDA is known to cause loss of the cells in the GCL and a reduction in the thickness of the inner plexiform layer (IPL) without affecting other retinal layers (18). To observe dividing cells, we injected BrdUrd into the vitreous chamber (30 nmol) and i.p.…”

Section: Mü Ller Glia Could Be Endogenous Progenitorsmentioning

confidence: 99%

Potential for neural regeneration after neurotoxic injury in the adult mammalian retina

Ooto

Akagi

Kageyama

et al. 2004

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

415

357

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It has long been believed that the retina of mature mammals is incapable of regeneration. In this study, using the N-methyl-Daspartate neurotoxicity model of adult rat retina, we observed that some Mü ller glial cells were stimulated to proliferate in response to a toxic injury and produce bipolar cells and rod photoreceptors. Although these newly produced neurons were limited in number, retinoic acid treatment promoted the number of regenerated bipolar cells. Moreover, misexpression of basic helix-loop-helix and homeobox genes promoted the induction of amacrine, horizontal, and rod photoreceptor specific phenotypes. These findings demonstrated that retinal neurons regenerated even in adult mammalian retina after toxic injury. Furthermore, we could partially control the fate of the regenerated neurons with extrinsic factors or intrinsic genes. The Mü ller glial cells constitute a potential source for the regeneration of adult mammalian retina and can be a target for drug delivery and gene therapy in retinal degenerative diseases.

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“…Although activation of these receptors constitutes a physiological phenomenon, hyperstimulation of NMDA and non-NMDA type ionotropic receptors can lead to cell death. Indeed, a number of previous studies have reported that glutamate and its receptor agonists such as NMDA and KA hyper-stimulate glutamate receptors ("excitotoxicity") and contribute to retinal damage (10,(17)(18)(19)(20)(21)(22)(23)(24)(25). In addition, elevated levels of glutamate and glutamate-mediated excitotoxicity have been implicated in ganglion cell loss in animals models for retinal ischemia (7,26,27), axonal injury (28), and glaucoma (6,29).…”

Section: Introductionmentioning

confidence: 99%

Plasminogen activators promote excitotoxicity‐induced retinal damage

2005

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Increased levels of extracellular L-glutamate have been suggested to play a role in retinal damage in a number of blinding diseases such as glaucoma and diabetic retinopathy. Although glutamate can cause retinal damage, in part, by hyper-stimulating its receptors ("excitotoxicity"), the down-stream events that lead to retinal damage are poorly understood. In this study, we injected kainic acid (KA), a glutamate receptor agonist that specifically hyper-stimulates non-NMDA-type receptors, into the vitreous humor of CD-1 mice and have investigated the role of plasminogen activators (PAs) [tissue plasminogen activator (tPA) and urokinase plasminogen activator (uPA)] in excitotoxicity-induced retinal damage. Injection of KA into the vitreous humor led to an up-regulation in tPA and an induction in uPA activity in the retina and this was associated with activation of zymogen plasminogen to active plasmin. Immunocytochemical analysis indicated that retinal ganglion cells (RGCs), constitutively, express tPA and release it into the extracellular space upon KA injection. Immunocytochemical analysis also indicated an increase in uPA in the nerve fiber layer after KA injection which was absent in the control retinas. These events were associated with apoptotic death of cells initially in the ganglion cell layer and subsequently in the inner and outer nuclear layer, associated with loss of both RGCs and amacrine cells. These phenomena were inhibited when recombinant plasminogen activator inhibitor (rPAI-1) or tPA-STOP were injected into the vitreous humor with KA, whereas a plasmin inhibitor, alpha-2-antiplasmin, failed to attenuate KA-induced retinal damage. Taken together, these results suggest that inhibition of plasminogen activators might attenuate retinal damage in blinding retinal diseases in which hyper-stimulation of glutamate receptors is implicated as a causative factor to retinal damage.

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N-methyl-D-aspartate-induced neurotoxicity in the adult rat retina

Cited by 259 publications

References 38 publications

Glutamate excitotoxicity in glaucoma: truth or fiction?

Glutamate excitotoxicity in glaucoma: truth or fiction?

Potential for neural regeneration after neurotoxic injury in the adult mammalian retina

Plasminogen activators promote excitotoxicity‐induced retinal damage

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