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Leonard A Levin

Publications and source records attributed to Leonard A Levin.

32 records · Page 2Linked to original sources
PubMed2003

Pathophysiology of the optic neuropathy associated with Friedreich ataxia.

OBJECTIVES: To describe the optic neuropathy associated with the genetic defect in Friedreich ataxia and suggest a pathophysiologic mechanism. METHODS: An experimental model of retinal ganglion cell death in the presence of metal chelation was used to test a hypothetical mechanism for the optic neuropathy of Friedreich ataxia. RESULTS: Study of cultured rat retinal ganglion cells suggests that abnormal regulation of intracellular iron levels could increase sensitivity to reactive oxygen species and lead to cell death in these metabolically active tissues. CONCLUSION: We hypothesize that decreased expression of frataxin, the mutated gene in Friedreich ataxia, could cause an optic neuropathy by increasing the sensitivity of retinal ganglion cells to oxidative stress.

Animals↗
PubMed2003

Retinal ganglion cells and neuroprotection for glaucoma.

Neuroprotection is a therapeutic strategy directed at keeping retinal ganglion cells (RGCs) alive and functional. This article discusses three commonly asked questions about neuroprotection and attempts to answer them in the context of our current understanding of the pathophysiology of RGC loss in glaucomatous optic neuropathy.

Cytoprotection↗
PubMed2003

The morphology of an infarct in nonarteritic anterior ischemic optic neuropathy.

OBJECTIVE: The mechanism by which nonarteritic anterior ischemic optic neuropathy (NAION) causes an infarct in the optic nerve is controversial. We studied the three-dimensional anatomic configuration of a NAION infarct to better elucidate its pathophysiology. DESIGN: Case report with clinicopathologic correlation. METHODS: Serial sections of the optic nerve from a previously reported patient diagnosed with NAION 20 days before death were studied. Every fourth slide was stained with hematoxylin-eosin, photographed, and digitized. NIH Image 1.62 was used to reconstruct the nerve in all three dimensions, and the infarct morphology was analyzed. MAIN OUTCOME MEASURES: Morphology of the reconstructed optic nerve infarct. RESULTS: The area of axonal loss within each section of the optic nerve was identified and reconstructed. The loss was in the superior part of the nerve, encircling the central retinal artery at its greatest extent. Remaining areas of the nerve appeared healthy, and, notably, the periphery of the uninvolved inferior portion of the nerve was normal. Three-dimensional analysis revealed two distinct areas of infarct at the posterior extent of the lesion which coalesced toward the center of the lesion and finally tapered as the infarct reached the optic nerve head. Sagittal reconstructions gave the appearance of a two-pronged fork posteriorly connecting to a single "handle" anteriorly. There was no obvious correlation between the configuration of the infarct and any single vascular territory. The total length of the nerve involved by the infarct was approximately 1.5 mm. CONCLUSIONS: The morphology of this NAION infarct is not consistent with disease of large or small vessels and, more likely, represents a form of compartment syndrome that causes tissue ischemia.

Aged↗
PubMed2003

Amplification of a reactive oxygen species signal in axotomized retinal ganglion cells.

Retinal ganglion cells (RGCs) undergo apoptosis after axonal injury. Elucidation of the sequence of intracellular events proximal to caspase activation may allow development of effective neuroprotective strategies. In this study, we explored the role that reactive oxygen species may have in signaling RGC apoptosis after axonal injury. Using the fluorescent probe dihydroethidium, we were able to measure intracellular superoxide anion production. We found that axotomized RGCs exposed to oxidative stress exhibited a secondary superoxide burst. The broad-spectrum caspase inhibitor Z-Val-Ala-DL-Asp-fluoromethyl ketone did not block the burst, suggesting it is proximal to caspase activation, but it was inhibited by cycloheximide, consistent with a requirement for protein synthesis. These results are consistent with RGC axotomy inducing synthesis of one or more proteins that mediate oxidative amplification. This could be an early event in signaling of RGC apoptosis after axonal injury.

Amino Acid Chloromethyl Ketones↗
PubMed2003

The effects of oxidative stress on mitochondrial transmembrane potential in retinal ganglion cells.

Retinal ganglion cells (RGCs) are central neurons that undergo apoptosis after axonal injury. As the relationship between mitochondrial and oxidative signaling of apoptosis in neuronal systems is unclear, we sought to achieve a better understanding of the interplay of these two pathways by investigating the effect of direct oxidative stress on mitochondrial membrane potential in cultured RGCs, as measured with the dual-emission probe JC-1. Treatment with hydrogen peroxide caused RGC mitochondrial depolarization. Several pharmacological treatments were used to define the mechanism. Whereas cycloheximide, tris(2-carboxyethyl)phosphine, and cyclosporin A were unable to prevent the depolarization, bongkrekic acid significantly reduced the severity of the depolarization. This suggests that the hydrogen peroxide-induced depolarization may act through mitochondrial permeability transition pore opening independent of thiol oxidation, and may be preventable under certain conditions.

Animals↗
PubMed2003

Cell-type-specific opening of the retinal ganglion cell mitochondrial permeability transition pore.

PURPOSE: To study the role of the mitochondrial permeability transition pore (PTP) in apoptosis of axotomized retinal ganglion cells (RGCs) in vitro. METHODS: Primary rat retinal cultures containing DiI-labeled RGCs were treated with pharmacological agents that modulate the PTP. Ratiometric imaging of the mitochondrial membrane potential (DeltaPsi(m)) were conducted on similarly treated cultures, with the dual-emission probe JC-1, and the correlation with the results of the viability experiments were determined. RESULTS: The peripheral benzodiazepine receptor agonist PK11195 induced RGC death, but this was not inhibited by cyclosporin A (CsA), which normally maintains the PTP in the closed configuration. Paradoxically, the combination of CsA and PK11195 caused massive RGC death and decreased DeltaPsi(m), suggesting aberrant regulation of the PTP in these cells. Imaging of DeltaPsi(m) revealed morphologic changes in the mitochondria after depolarization, characterized by formation of ringlike bodies, and similar to that with the potassium ionophore valinomycin. There were no such findings with other retinal neurons or neuronally differentiated PC-12 cells. The anomalous RGC death was independent of caspase activation or reactive oxygen species production. CONCLUSIONS: These results suggest an aberrant opening of the RGC PTP and could be the result of structural differences in its components or its interaction with intracellular ligands. Unique RGC PTP behavior could underlie the pathophysiology of those mitochondrial diseases in which RGCs are specifically affected (e.g., Leber hereditary optic neuropathy).

Animals↗
PubMed2002

Treatment of ischemic optic neuropathy.

Ischemic damage of the optic nerve has no proven effective treatment. While ischemia related to vasculitis (arteritic) is treated with systemic corticosteroids, the primary goal is to prevent further damage, either in the affected or fellow eye. Thrombolytic or anticoagulation supplementive therapy may be considerations for the future. In the more common idiopathic (nonarteritic) form (NAION), multiple attempts at therapy, including systemic corticosteroids, anticoagulants and antiplatelet agents, diphenylhydantoin, hyperbaric oxygen, and optic nerve sheath decompression have been unsuccessful. The use of levodopa has been proposed but is unproven. Megadose intravenous corticosteroid therapy has not been studied in a systematic way. Neuroprotective strategies are under intense investigation for optic neuropathies including NAION, and clinical trials in humans are in progress. Optic nerve regeneration studies are ongoing in animals. Prophylaxis in NAION is unproven.

Adrenal Cortex Hormones↗
PubMed2002

Current understanding of neuroprotection in glaucoma.

The most common optic neuropathy is glaucomatous optic neuropathy, distinguished by a distinctive and progressive excavation of the optic nerve head without significant pallor of the remaining neuroretinal rim. Neuroprotection is a novel strategy for treating disorders that affect the nervous system by preventing death of neurons. In glaucomatous optic neuropathy, the neurons that die are retinal ganglion cells. This article reviews the recent basic science relevant to neuroprotection, particularly with respect to retinal ganglion cell death in glaucomatous and other optic neuropathies.

Cell Death↗