Biomedical subjects

R Naskar

Publications and source records attributed to R Naskar.

11 recordsLinked to original sources

PubMed2001

New horizons in neuroprotection.

Glaucoma is a leading cause of blindness worldwide and the second leading cause of irreversible blindness in the USA. The most common form of glaucoma, primary open angle glaucoma, is characterized by a chronically elevated intraocular pressure in the absence of any demonstrable structural abnormalities in the eye. The pathologic hallmark of glaucomatous optic neuropathy is the selective death of retinal ganglion cells associated with structural changes in the optic nerve head. Recent discoveries suggest a role for nitric oxide, glutamate, apoptosis, and others, in the pathophysiology of this neuropathy. These newer discoveries are addressed in this article.

Apoptosis↗

PubMed2001

Excitotoxicity can be mediated through an interaction within the optic nerve; activation of cell body NMDA receptors is not required.

Axonal trauma leads to a series of pathologic events that can culminate in neuronal death. Although the precise mechanisms of retinal ganglion cell death after optic nerve crush in the rat model have not been elucidated, glutamate antagonists can protect retinal ganglion cells after optic nerve axotomy. We therefore explored whether a glutamate congener was toxic if applied directly within the optic nerve, or if toxicity depended upon an interaction at the cell body level. NMDA reduced retinal ganglion cell survival when applied directly into the rat optic nerve. Glutamate can be toxic if administered within the optic nerve; a direct effect at the cell body is not necessary. Future work will help to additionally unravel the steps by which axotomy induces excitotoxic damage to ganglion cells, and perhaps indicate protective interventions.

Animals↗

PubMed2000

Concurrent downregulation of a glutamate transporter and receptor in glaucoma.

PURPOSE: Elevated levels of extracellular glutamate have been implicated in the pathophysiology of neuronal loss in both central nervous system and ophthalmic disorders, including glaucoma. This increase in glutamate may result from a failure of glutamate transporters, which are molecules that ordinarily regulate extracellular glutamate. Elevated glutamate levels can also lead to a perturbation in glutamate receptors. The hypothesis for the current study was that glutamate transporters and/or receptors are altered in human glaucoma. METHODS: Immunohistochemical analyses of human eyes with glaucoma and control eyes were performed to evaluate glutamate receptors and transporters. These molecules were also assayed in rat eyes injected with glial-derived neurotrophic factor (GDNF). RESULTS: Glaucomatous eyes had decreased levels of both the glutamate transporter, excitatory amino acid transporter (EAAT)-1, and the glutamate receptor subunit N-methyl-D-aspartate (NMDA)-R1. Eyes treated with GDNF had elevated levels of both EAAT1 and NMDAR1. CONCLUSIONS: The loss of EAAT1 in glaucoma may account for the elevated level of glutamate found in glaucomatous vitreous and lead to a compensatory downregulation of NMDAR1. Inasmuch as GDNF can increase levels of both EAAT1 and NMDAR1, it may be a useful therapeutic approach to restore homeostatic levels of these in glaucoma.

ATP-Binding Cassette Transporters↗

PubMed2000

Depression of retinal glutamate transporter function leads to elevated intravitreal glutamate levels and ganglion cell death.

PURPOSE: Elevated levels of extracellular glutamate have been implicated in the pathophysiology of neuronal loss in both central nervous system and ophthalmic disorders, including glaucoma. This increase in glutamate may result from a failure of glutamate transporters (molecules that ordinarily regulate extracellular glutamate; E:xcitatory A:mino A:cid T:ransporter; EAAT). Elevated glutamate levels can also lead to alterations in glutamate receptor expression. It was hypothesized that selective blockade of glutamate transporters would be toxic to retinal ganglion cells. METHODS: Glutamate transporters were blocked either pharmacologically or with subtype-specific antisense oligonucleotides against EAAT1. Glutamate levels, transporter levels and ganglion cell survival were assayed. RESULTS: Pharmacological inhibition of glutamate transporters with either an EAAT2 specific inhibitor or a nonspecific inhibitor of all the subtypes of transporters was toxic to ganglion cells. Treatment with oligonucleotides against the glutamate transporter EAAT1 decreased the levels of expression of the transporter, increased vitreal glutamate, and was toxic to ganglion cells. CONCLUSIONS: These results demonstrate that normal function of EAAT1 and EAAT2 is necessary for retinal ganglion cell survival and plays an important role in retinal excitotoxicity. Manipulation of retinal glutamate transporter expression may become a useful tool in understanding retinal neuronal loss.

ATP-Binding Cassette Transporters↗

PubMed2000

Ganglion cell loss after optic nerve crush mediated through AMPA-kainate and NMDA receptors.

PURPOSE: Glutamate antagonists can block ganglion cell death due to optic nerve crush. Although most investigators have focused on blockade of the N-methyl-D-aspartate (NMDA) subtype of glutamate receptor, we have chosen to evaluate the efficacy of blockade of the AMPA-kainate (KA) receptor in this experimental paradigm. METHODS: The optic nerves of rats were crushed, and ganglion cell survival was assessed. Groups of animals were treated with an NMDA antagonist, an AMPA-KA antagonist, or both. RESULTS: The AMPA-KA antagonist DNQX was more effective, although not additive in preserving retinal ganglion cells after optic nerve crush than the NMDA antagonist MK801. CONCLUSIONS: Activation of the AMPA-KA subtype of glutamate receptor may play a role in glutamate-mediated cell death after optic nerve crush.

Animals↗

PubMed1999

Thy-1 is critical for normal retinal development.

In the mammalian retina, Thy-1, the most abundant mammalian neuronal surface glycoprotein, is found predominantly if not exclusively on retinal ganglion cells. We hypothesized that Thy-1 plays a significant role in retinal development. Neurite outgrowth of retinal ganglion cells from Thy-1(-) mice over multiple substrates was compared to that seen with wild-type controls. Adult mouse retinas were histologically compared between Thy-1(-) and three strains of Thy-1 positive mice. Thy-1(-) retinal ganglion cells had significantly less neurite outgrowth than controls. The inner nuclear, inner plexiform, ganglion cell and outer segment/pigment epithelium layers were thinner in Thy-1(-) retinae than in controls. Thy-1 appears to be critical for normal retinal development.

Animals↗

PubMed1999

[The excitotoxicity theory of glaucoma].

Glaucoma can be defined as a disease in which one of the pathophysiological consequences of raised intra-ocular pressure is damage of the optic nerve, and subsequently the loss of retinal ganglion cells (RGCs). One of the main aims of modern glaucoma therapy is to alter the intraocular pressure, either surgically or pharmacologically. Recently it was shown that the vitreous of glaucoma patients contains increased levels of glutamate (27 microM as compared to 11 microM in controls). This concentration of glutamate is sufficient to induce retinal ganglion cell death. The rise in intraocular pressure is probably the initial insult, which enhances the increase or release of glutamate. Although the increase in intravitreal glutamate levels is an accompanying feature of glaucoma, it could contribute to the loss of retinal ganglion cells in humans itself. Therefore, despite efficient control of intra-ocular pressure, RGC's loss will continue resulting in further visual impairment, if the toxic effect of glutamate is not blocked. If it would be possible to understand the mechanism leading to excessive vitreous levels of glutamate in glaucoma or to block its toxic effects, then the resulting visual loss could be retarded. This review discusses various proposed mechanisms leading to intraocular glutamate toxicity and the role of neuroprotection in this disease. (Literature search by Medline).

Animals↗

PubMed1999

Saving the nerve from glaucoma: memantine to caspaces.

Three recent discoveries regarding the pathophysiology of human glaucoma are that retinal ganglion cells die by apoptosis, that nitric oxide synthase levels are altered, and that glutamate is elevated in the vitreous. These findings provide encouraging new avenues for the development of neuroprotective strategies to alleviate ganglion cell loss and blindness that accompanies this disease. In this article, we discuss some of these data, as well as potential therapies that may arise from these findings.

Animals↗

PubMed1997

Regenerating ganglion cell axons in the adult rat establish retinofugal topography and restore visual function.

The mechanisms of neuronal network response to axotomy are poorly understood. In one of the favoured models used to study the fate of injured neurons in the adult rat visual system, appreciable numbers of retinal neurons survive optic nerve injury under conditions of microglia-targeted neuroprotection. Rescued neurons can regenerate their axons and become target-dependently stabilised after reconnection with their natural visual centres by means of a peripheral nerve graft, which, in addition to guidance, actively supports axonal growth. The mechanisms that control regenerative axonal growth and resynaptogenesis include coordinated cell-cell interactions between growing neurites and target cells in order to establish a meaningful reconnectivity. Here the function of the regenerating visual circuitry was first studied by monitoring the ability of animals to discriminate spatial patterns, and second by recording visual evoked cortical potentials (VEPs) in the same animals. These functions were correlated with neuroanatomical studies of the retinotopic organisation of regenerating axons. To achieve these goals, adult rats were behaviourally trained in a Y-maze to discriminate between vertical and horizontal stripes. Both optic nerves were transected, and the regenerating axons of one optic nerve were guided into the area of optic tract with a peripheral nerve graft according to the protocols of neuroprotection and simultaneous grafting, in order to enable large numbers of axons to reinnervate the major visual targets in the midbrain and thalamus. Postoperative testing of the animals showed a marked improvement of visual perception and behaviour. The VEPs of the same animals were measurable indicating a restoration of the visual circuitry including the ascending corticopedal connections. Neuroanatomical assessment of the fibre topography within the graft and the area of termination revealed a rough topographic organisation that may account for restoration of the function. These results suggest that interrupted central pathways can be functionally reconnected by providing a neuroprotective environment in combination with peripheral nerve grafts to bypass lesions.

Animals↗

PubMed1996

Timing of fiber arrival and dennervation of postsynaptic neurons is required for restoration of visual perception by regenerating axons.

Axotomized CNS neurons, whose regenerating axons are guided to their natural target areas in the brain with the aid of peripheral nerve grafts, are capable of establishing synaptic contacts with normal morphological and electrophysiological properties. The present study was undertaken to analyse the functional significance of the reestablished synaptic contacts made by these regenerated retinofugal neurons. Adult rats were trained in a T-maze to obtain a food reward with the aid of visual cues. One of their optic nerves was transected and the regenerating axons were guided into the optic tract with a peripheral nerve graft, in order to enable them to reinnervate the superior colliculus (SC) and thalamus. Postoperative testing of the animals showed a drastic improvement of visual perception. The protocol of dennervation of the SC (prior to, simultaneous or with a delay with respect to fiber arrival) determined the performance of the animals. Rats belonging to the first two groups performed almost as well as they did prior to the transplantation. The functional integrity of the retina was assessed by electroretinography (ERG) which revealed typical rod spectral sensitivity at 380 and 500 nm, but reduced responsiveness to illumination. In accordance, neuroanatomical assessment of the retinal ganglion cells revealed that about 15% of the axotomized neurons contributed to regeneration of axons. These findings show that a restricted population of retinofugal axons of capable of restoring higher visual functions such as light-discrimination-behaviour in the adult rat. Prerequisites for the restoration of visual perception are first the preservation of the intraretinal integrity, and second the temporal matching of fiber arrival and dennervation of postsynaptic neurons.

Animals↗

PubMed1996

Evidence for glaucoma-induced horizontal cell alterations in the human retina.

In this study we investigated changes to horizontal cells in human retinae affected by glaucoma. Glaucoma is characterized by raised intraocular pressure and is responsible for retinal ganglion cell and, possibly, photoreceptor degeneration. It was therefore assumed that horizontal cells might also be affected. The carbocyanine dye DiI was placed at discrete points on fixed, whole-mounted retinae obtained from normal and glaucomatous patients. After allowing 6-24 weeks for intramembranous diffusion within the lipid layers of the nerve cells and, therefore, fluorescent labeling, we measured horizontal cell soma and dendritic field sizes. Selected cells were then embedded in Araldite and cut at 4 microns. Horizontal cells in glaucomatous eyes appeared larger and had a granulated outline as compared with cells from normal retinae. Analysis of the mean cell soma size indicated that cells were 26% larger in the glaucomatous retinae and that this increase was significantly different from that seen in normal retinae (P < 0.05). The dendritic field size was unaffected (P > 0.05). As seen in cross section there was a clear loss of photoreceptor outer segments, and shrunken silhouettes of photoreceptor inner segments with pyknotic nuclei were observed. It is proposed that the increase in some size is indicative of horizontal cell responses that are likely to culminate in degeneration as a result of heightened intraocular pressure. In addition, this paper provides further evidence that photoreceptors are affected by advanced glaucoma.

Carbocyanines↗