Neuroprotection in Relation to Retinal Ischemia and Relevance to Glaucoma

Osborne, Neville N.; Ugarte, Marta; Chao, Michael J.; Chidlow, Glyn; Bae, J.H; Wood, J. K.; Nash, Mark S.

doi:10.1016/s0039-6257(99)00044-2

Cited by 357 publications

(224 citation statements)

References 194 publications

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“…5 Substances, for example, which prevent an unusual rise in calcium and/or free radicals in an insulted neurone are likely to act as neuroprotectants. 5 Although we have not tested whether 8-0H-DPAT acts as a free radical scavenger, studies have been conducted to determine whether it can act as a 'calcium channel blocker'. Initial experiments were carried out on rat cortical cultures as described elsewhere.…”

Section: ---------------------------------- - 20mentioning

confidence: 99%

5-Hydroxytryptamine1A agonists: Potential use in glaucoma. Evidence from animal studies

Osborne

Wood

Melena

et al. 2000

Eye

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Section: ---------------------------------- - 20mentioning

confidence: 99%

5-Hydroxytryptamine1A agonists: Potential use in glaucoma. Evidence from animal studies

Osborne

Wood

Melena

et al. 2000

Eye

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“…Although the mechanisms that underlie retinal damage in these diseases are poorly understood, previous studies have suggested that excitatory amino acid (EAA) such as L-glutamate might play a role (6)(7)(8)(9)(10)(11). Accumulation of glutamate into the extracellular space activates two major classes of receptors, the ionotropic (N-methyl-Daspartate [NMDA], alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid [AMPA]/ kainic acid [KA]-type) and the G-protein-coupled metabotropic receptors (12)(13)(14). A number of cells including ganglion cells and amacrine cells in the retina express these receptors (15,16).…”

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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“…A number of different methods have been identified, and these include: intravitreal injection of ionotropic glutamate receptor agonists (eg NMDA or kainate), 18,19 raising the extracellular glutamate level by blocking uptake into Mü ller cells, 20 and by causing retinal ischaemia. 21 The cause of cell death in all of these models is thought to essentially occur via the same process, that is, excessive depolarisation caused by overstimulation of ionotropic glutamate receptors. 22 As well as ganglion cells, however, other cells, particularly subsets of amacrine cells, are also affected in such instances.…”

Section: Introductionmentioning

confidence: 99%

Optic nerve and neuroprotection strategies

Osborne

Chidlow

Layton

et al. 2004

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Background Experimental studies have yielded a wealth of information related to the mechanism of ganglion cell death following injury either to the mylinated ganglion cell axon or to the ganglion cell body. However, no suitable animal models exist where injury can be directed to the optic nerve head region, particularly the unmylinated ganglion cell axons. The process of relating the data from the various animal models to many different types of optic neuropathies in man must, therefore, be cautious. Results Extensive studies on the isolated optic nerve have yielded valuable information on the way white matter is affected by ischaemia and how certain types of compounds can attenuate the process. Moreover, there are now persuasive data on how ganglion cell survival is affected when the ocular blood flow is reduced in various animal models. As a consequence, the molecular mechanisms involved in ganglion cell death are fairly well understood and various pharmacological agents have been shown to blunt the process when delivered before or shortly after the insult. Conclusions A battery of agents now exist that can blunt animal ganglion cell death irrespective of whether the insult was to the ganglion cell body or the mylinated axon. Whether this information can be applied for use in patients remains a matter of debate, and major obstacles need to be overcome before the laboratory studies may be applied clinically. These include the delivery of the pharmacological agents to the site of ganglion cell injury and side effects to the patients. Moreover, it is necessary to establish whether effective neuroprotection is only possible when the drug is administered at a defined time after injury to the ganglion cells. This information is essential in order to pursue the idea that a neuroprotective strategy can be applied to a disease like glaucoma, where

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Neuroprotection in Relation to Retinal Ischemia and Relevance to Glaucoma

Cited by 357 publications

References 194 publications

5-Hydroxytryptamine1A agonists: Potential use in glaucoma. Evidence from animal studies

5-Hydroxytryptamine1A agonists: Potential use in glaucoma. Evidence from animal studies

Plasminogen activators promote excitotoxicity‐induced retinal damage

Optic nerve and neuroprotection strategies

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