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Biomedical subjects

E B Dreyer

Publications and source records attributed to E B Dreyer.

At least 19 recordsLinked to original sources
PubMed1997

Vitreous body glutamate concentration in dogs with glaucoma.

OBJECTIVE: To analyze the vitreal amino acid concentrations in dogs with breed-related primary glaucoma to determine whether excitotoxic amino acids associated with retinal genglion cell death in other species were present in affected dogs. SAMPLES: 11 normal control and 10 glaucomatous canine eyes. PROCEDURE: Amino acid analyses were performed by high-pressure liquid chromatography in masked manner. RESULTS: Eyes from dogs with primary glaucoma had significantly high vitreal glutamate concentration, compared with values for eyes of clinically normal control dogs. Mean (+/-SD) glutamate concentrations were 31.7 +/- 12.4 and 6.9 +/- 6.3 microM in glaucomatous and normal eyes, respectively (P < 0.0001). Eyes from dogs with glaucoma also had lower vitreal glycine (37.0 +/- 17.0 vs 59.4 +/- 28.2 microM; P < 0.043) and higher of vitreal tryptophan (39.0 +/- 22.8 vs 17.5 +/- 11.2 microM; P < 0.012) concentrations, compared with values for normal eyes. CONCLUSION: Glutamate concentration potentially toxic to retinal ganglion cells is associated with the pathogenesis of primary glaucoma in dogs. Increased glutamate concentration provides evidence of an ischemic mechanism for retinal ganglion cell death and optic nerve atrophy in dogs with glaucoma. CLINICAL RELEVANCE: The emphasis on reduction and normalization of high intraocular pressure as the primary focus of treatment for glaucoma in dogs should be augmented by other therapeutic approaches.

Amino Acids↗
PubMed1997

Excitatory mechanisms in retinal ganglion cell death in primary open angle glaucoma (POAG).

Glaucoma is a leading cause of blindness worldwide and the second leading cause of irreversible blindness in the United States. 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, generally attributed to an elevated intraocular pressure. However, the histopathology of glaucomatous injury is strikingly similar to the pattern seen with the administration of toxic levels of glutamate. We have found that glaucoma is associated with elevated levels of intraocular glutamate-to a level toxic to ganglion cells. We propose that an elevation of vitreal glutamate may be responsible, at least in part, for the loss of ganglion cells seen in open angle glaucoma.

Animals↗
PubMed1997

The role of neuronal and endothelial nitric oxide synthase in retinal excitotoxicity.

PURPOSE: Nitric oxide synthase (NOS) plays an essential role in neuronal function and is critical in the brain for normal and pathologic responses to glutamate. The role of NOS in the retina is less well understood. The retina provides an experimental system in which the intrinsic circuitry is well defined; retinal excitotoxic damage has been well characterized. METHODS: To determine whether neuronal NOS (nNOS) and endothelial NOS (eNOS) are critical in excitotoxic damage in the retina, nNOS- and eNOS-deficient mice were subjected to intravitreal injections of N-methyl-D-aspartate (NMDA) or to arterial occlusions. RESULTS: Retinal ganglion cells in the nNOS-deficient mouse were relatively resistant to NMDA and to arterial occlusion. In contrast, the damage in the eNOS-deficient mouse retina was not distinguishable from that in control animals. Preinjection with an NOS inhibitor was partially protective. CONCLUSIONS: The presence of nNOS is a prerequisite for the full expression of excitotoxicity in the retina; eNOS does not appear to play a significant role.

Animals↗
PubMed1996

Elevated glutamate levels in the vitreous body of humans and monkeys with glaucoma.

OBJECTIVE: To explore the possibility that the excitatory amino acid glutamate might be associated with the disease process of glaucoma, which is characterized by the death of retinal ganglion cell neurons and subsequent visual dysfunction. METHODS: Amino acid analyses were performed on vitreous specimens that were obtained from patients who were undergoing cataract extraction. Samples were collected prospectively from those patients who sustained inadvertent rupture of the posterior capsule between 1988 and 1993. An additional set of specimens, obtained from both eyes of monkeys, was analyzed; in these monkeys, glaucoma had been experimentally induced in one eye only. RESULTS: A twofold elevation in the level of glutamate was detected in the vitreous body of the group of patients with glaucoma when compared with that in a control population of patients with cataracts only. An even greater elevation of the glutamate level was found in the vitreous body of glaucomatous eyes of monkeys when compared with that in control eyes. No statistical differences were detected among other amino acid levels from the vitreous body of glaucomatous and nonglaucomatous eyes in humans or monkeys. CONCLUSIONS: The excitatory amino acid glutamate is found in the vitreous body of glaucomatous eyes at concentrations that are potentially toxic to retinal ganglion cells. The increased level of this known neurotoxin is consistent with an "excitotoxic" mechanism for the retinal ganglion cell and optic nerve damage in glaucoma. Therapies to protect neurons against glutamate toxic effects may prove to be useful in the management of this blinding disease.

Aged↗
PubMed1996

Retinal Thy-1 expression during development.

PURPOSE: To evaluate the developmental expression of Thy-1 in the retina. Thy-1, the most abundant mammalian neuronal surface glycoprotein, is likely to play a significant role in retinal development. In the mammalian retina, it is found predominantly, if not exclusively, on retinal ganglion cells. METHODS: Rat retinae of various ages were stained immunohistochemically for Thy-1 with 2G12, a monoclonal Thy-1 antibody. Sections were analyzed digitally to quantify bound antibody. Using semiquantitative reverse transcription-polymerase chain reaction (RT-PCR), the expression of Thy-1 protein was compared with the levels of mRNA detected. RESULTS: Thy-1-dependent fluorescence was detected in rat retinae from birth, albeit at low levels. Thy-1 labeling was localized predominantly to the ganglion cell layer. Minimal, fine patterns of linear and reticular fluorescence were noted in the inner nuclear layer. Thy-1 levels reached a maximal level at approximately postnatal day 14. RT-PCR measurements showed a similar time course for the increase in Thy-1 expression. CONCLUSIONS: The Thy-1 antigen is present in the inner retina at birth. Its level increases steadily after birth and peaks during the second week of life. Thy-1 expression is approximately coterminous with synaptogenesis of the inner plexiform layer and may play a role in synaptogenesis of the inner retina or in other developmental milestones in the formation of the visual system.

Animals↗
PubMed1996

Chronic low-dose glutamate is toxic to retinal ganglion cells. Toxicity blocked by memantine.

PURPOSE: It is well known that acute exposure to high concentrations of glutamate is toxic to central mammalian neurons. However, the effect of a chronic, minor elevation over endogenous glutamate levels has not been explored. The authors have suggested that such chronic exposure may play a role in glaucomatous neuronal loss. In the current study, they sought to explore whether a chronic, low-dose elevation in vitreal glutamate was toxic to retinal ganglion cells and whether this toxicity could be prevented with memantine, a glutamate antagonist. METHODS: Rats were injected serially and intravitreally with glutamate to induce chronic elevations in glutamate concentration. A second group of rats was treated with intraperitoneal memantine and glutamate. Control groups received vehicle injection with or without concurrent memantine therapy. After 3 months, the animals were killed, and ganglion cell survival was evaluated. RESULTS: Intravitreal injections raised the intravitreal glutamate levels from an endogenous range of 5 to 12 microM glutamate to 26 to 34 microM. This chronic glutamate elevation killed 42% of the retinal ganglion cells after 3 months. Memantine treatment alone had no effect on ganglion cell survival. However, when memantine was given concurrently with low-dose glutamate, memantine was partially protective against glutamate toxicity. CONCLUSIONS: These data suggest that minor elevations in glutamate concentration can be toxic to ganglion cells if this elevation is maintained for 3 months. Furthermore, memantine is efficacious at protecting ganglion cells from chronic low-dose glutamate toxicity.

Animals↗
PubMed1996

Inhaled steroids: effect on intraocular pressure in patients without glaucoma.

OBJECTIVE: To evaluate the risk of intraocular pressure (IOP) elevation in patients receiving inhaled steroid therapy. DESIGN: Prospective study. SETTING: Four private practices in New Jersey. PATIENTS: A total of 187 patients (99 men and 88 women) with no documented history of glaucoma about to begin inhaled steroid therapy for various pulmonary conditions were enrolled. Of the 187, 183 were followed at 12 weeks. INTERVENTIONS: Measurement of the IOP with the Tono-Pen before therapy was started and 12 weeks after therapy was started. OUTCOME MEASURE: IOP. RESULTS: No significant rise in IOP was observed. No patient had a rise in IOP greater than 4 mm Hg. CONCLUSIONS: Although isolated case reports indicate a definite risk of glaucoma in the presence of inhaled steroid therapy, the risk appears to be small.

Administration, Inhalation↗
PubMed1996

Systemic L-kynurenine administration partially protects against NMDA, but not kainate-induced degeneration of retinal ganglion cells, and reduces visual discrimination deficits in adults rats.

PURPOSE: Kynurenic acid (KYNA), an endogenous tryptophan metabolite, is an N-methyl-D-aspartate (NMDA) antagonist active at the glycine-binding site of the NMDA-receptor complex. The authors investigated whether systemic administration of a biochemical precursor of KYNA, L-kynurenine (L-Kyn), could block NMDA- or kainic acid (KA)-induced cell death in adult rat retinal ganglion cells (RGCs) and protect NMDA-treated animals from lesion-induced visual deficits. METHODS: Rats were injected with 20-nmol NMDA or 5-nmol KA intraocularly. To quantify the number of surviving RGCs, the retrograde tracer horseradish-peroxidase was injected into the superior colliculus contralateral to the lesioned eye. Surviving RGCs were counted on wholemounted retinae in a centroperipheral gradient, as well as in the four quadrants, using a computer-assisted image analysis system. RESULTS: The NMDA-injections resulted in an approximately 82% RGC loss in the adult rat retina compared with control retinae and a cell loss of approximately 50% in KA-treated retinae. Pretreatment with L-Kyn significantly reduced NMDA-induced RGC degeneration to values of approximately 60%, but KA toxicity was not significantly affected by L-Kyn pretreatment. Intraocular injections of NMDA resulted in an impairment of visual discrimination behavior, which partially recovered within a period of approximately 3 weeks. However, when treated systemically with L-Kyn, brightness discrimination was significantly improved as compared with NMDA-treated rats. CONCLUSIONS: These findings show that systemic administration of L-Kyn in adult rats can block NMDA-induced retinal ganglion cell death in vivo and preserves brightness discrimination performance.

Animals↗
PubMed1995

The coat protein gp120 of HIV-1 inhibits astrocyte uptake of excitatory amino acids via macrophage arachidonic acid.

The human immunodeficiency virus coat protein gp120 injures central mammalian neurons both in vitro and in vivo, and this observation may contribute, at least in part, to the neurological dysfunction associated with the acquired immunodeficiency syndrome. Recent work suggests that gp120 mediates neuronal damage predominantly via an indirect route involving activation of brain macrophages. We have previously shown that the stimulation of N-methyl-D-aspartate receptors by excitatory amino acids is essential for the neuronal injury observed with gp120. Here we show that gp120 impairs astrocyte uptake of excitatory amino acids and the excess glutamate thus engendered may contribute to the increased neuronal damage. We also studied the mechanism whereby gp120 inhibits the uptake of excitatory amino acids by astrocytes. We present data suggesting that at least one pathway involves a direct effect of gp120 on macrophages, which in turn release arachidonic acid, a known inhibitor of excitatory amino acid uptake by astrocytes. Our findings suggest that the observed effects on glia and neurons of gp120 may be secondary, at least in part, to its initial activation of macrophages.

Acquired Immunodeficiency Syndrome↗
PubMed1995

An astrocytic binding site for neuronal Thy-1 and its effect on neurite outgrowth.

Thy-1, a member of the immunoglobulin superfamily, is one of the most abundant glycoproteins on mammalian neurons. Nevertheless, its role in the peripheral or central nervous system is poorly understood. Certain monoclonal antibodies to Thy-1 promote neurite outgrowth by rodent central nervous system neurons in vitro, suggesting that Thy-1 functions, in part, by modulating neurite outgrowth. We describe a binding site for Thy-1 on astrocytes. This Thy-1-binding protein has been characterized by immunofluroesence with specific anti-idiotype monoclonal antibodies and by three competitive binding assays using (i) anti-idiotype antibodies, (ii) purified Thy-1, and (iii) Thy-1-transfected cells. The Thy-1-binding protein may participate in axonal or dendritic development in the nervous system.

Animals↗
PubMed1995

NMDA sensitivity is neurite enhanced.

Glutamate toxicity in retinal ganglion cells has been well documented both in vitro and in vitro, and may play a role in both normal neuronal development and a variety of pathological states. Glutamate receptors are found on cell bodies and neuronal processes, both axons and dendrites. Other work has suggested that one or more of these locales may play a more pronounced role in glutamate-mediated toxicity. We now report that N-methyl-D-aspartate (NMDA) is more toxic to retinal ganglion cells with neurites. Cells without neurites were relatively unaffected by glutamate or NMDA. Cells with longer neurites or more neurite branch points were more likely to sustain NMDA-mediated neurotoxicity. These observations suggest that glutamate-mediated loss may be mediated through NMDA receptors found on neurites, rather than through a direct effect on the cell body.

Animals↗
PubMed1995

Transcriptional or translational inhibition blocks low dose NMDA-mediated cell death.

Glutamate toxicity in nerve cells has been well documented and may play a role in a broad spectrum of neurological and ophthalmic diseases. Recent work in several laboratories has suggested that an apoptotic-like mechanism may be implicated in glutamate toxicity under certain circumstances. We therefore studied the effects of transcriptional and translational inhibition on glutamate-mediated cell death in retinal ganglion cells. We now report that either cycloheximide or actinomycin D can, even when added 2 h after the initial excitotoxic insult, save retinal ganglion cells from low dose glutamate toxicity. However, cycloheximide or actinomycin D are unable to prevent glutamate-mediated death at higher concentrations of excitotoxin. This result indicates that at low doses, the neurotoxic effects of glutamate may develop through an apoptotic-like mechanism.

Animals↗
PubMed1995

Effect of mitomycin C and fluorouracil-supplemented trabeculectomies on the anterior segment.

OBJECTIVES: To determine whether there is increased risk to the corneal endothelium when mitomycin C is used in trabeculectomy surgery instead of fluorouracil, and whether these agents play a role in accelerating cataract formation. DESIGN, SETTINGS, AND PARTICIPANTS: We analyzed the corneal endothelium and the lens preoperatively and postoperatively in 30 eyes of 21 patients who underwent either a fluorouracil- or mitomycin C-supplemented trabeculectomy. RESULTS: No significant differences were found between these two groups in the rate of cataract progression, magnitude of endothelial cell loss, or appearance of endothelial cell morphologic characteristics. Endothelial cell loss accounted for approximately 7% to 8% of the preoperative counts in both groups. In addition, four (27%) of 15 eyes in each group showed evidence of cataract progression as graded by the Lens Opacities Classification System II. CONCLUSION: Fluorouracil- and mitomycin C-supplemented trabeculectomies cause similar changes in the lens and corneal endothelium.

Aged↗