Superoxide Generation Explains Common Features of Optic Neuropathies Associated With Cecocentral Scotomas

The pathophysiology of some of the more common optic neuropathies associated with cecocentral scotomas might be explained by a unifying hypothesis. This hypothesis is based on clinical features of these optic neuropathies, laboratory studies of the pathophysiology of how retinal ganglion cells (RGCs) die, some of which is unpublished, and biochemistry of reactive oxygen species generation within some of these disorders. OPTIC NEUROPATHIES AND CECOCENTRAL SCOTOMAS Diseases of the optic nerve are associated with abnormalities of vision, primarily visual acuity, color vision, contrast sensitivity, and most relevant to this discussion, the visual field. The nature of the visual field defect usually reflects the location at which the disease affects the optic nerve. For example, glaucomatous optic neuropathy primarily affects RGC axons at the optic nerve head. A focal thinning of the optic disc will affect those axons which originated from RGCs defined by the pattern of the retinal nerve fiber layer (1). Compression of the chiasm from a pituitary adenoma that affects primarily crossing fibers will generate unilateral or bilateral temporal visual field defects. Cecocentral scotomas are distinctive in that there is visual field loss centrally, but there is involvement that includes the blind spot, that is, a temporal predominance. This is different from pure central loss which only involves the blind spot as a result of the defect itself being large enough to subsume it. What is interesting about diseases associated with cecocentral scotomas is that they are relatively few in number and share common clinical features. The main optic neuropathies with cecocentral scotomas are: Leber hereditary optic neuropathy (LHON) Nutritional optic neuropathy Toxic optic neuropathy Other hereditary optic neuropathies. My focus will be on the first 3, creating a hypothetical framework for understanding their pathophysiology. CLINICAL PRESENTATION OF CECOCENTRAL SCOTOMAS The optic neuropathies associated with cecocentral scotoma are painless and bilateral, and usually progressive. LHON is an exception in that the visual loss frequently starts unilaterally but eventually becomes bilateral in all cases. When only 1 eye is affected initially, the fellow eye follows within weeks to months although sometimes longer. Optic disc edema is unusual in the optic neuropathies associated with cecocentral scotomas. In LHON, there may be a swollen optic nerve head with telangiectatic small vessels, but it is not true disc edema because it does not show evidence of vascular leakage on fluorescein angiography. Occasionally, acute toxic or nutritional optic neuropathies show elevation of the disc. CECOCENTRAL SCOTOMAS AND PATHOPHYSIOLOGY A cecocentral scotoma is a visual field defect that can be thought of as representing a biomarker of an underlying pathophysiological process. The retinotopic distribution of the cecocentral scotoma classically has been believed to reflect damage to the papillomacular bundle. However, the papillomacular bundle is not a single well-defined set of axons but rather a concentration of axons that are primarily small in diameter and are within the area between the optic disc and the perifoveal macula (2). As pointed out by Plant and Perry (2) and others, the concept of the papillomacular bundle was a reverse induction from the clinical and histological findings associated with toxic optic neuropathy. It is tautologous that the papillomacular bundle is involved in similar diseases, that is, those with cecocentral scotomas. For the sake of convenience and common usage in the rest of this article, I will use the term papillomacular bundle to refer to the set of fibers arising from the foveal and parafoveal regions and approaching the temporal part of the optic disc, both directly and through an arcuate pathway. The critical assumption underlying the framework being developed is that the common clinical presentation of optic neuropathies associated with cecocentral scotomas implies a common pathophysiological process. Specifically, my hypothesis is that these disorders have in common the generation of superoxide anion, or superoxide (O2–). Superoxide is an oxygen-containing free radical generated within cells in various processes. Relevant to this hypothesis, one of the main sources of superoxide is the reaction of molecular oxygen (O2) with a free electron. Superoxide is reactive, and among its reactions is that with nitric oxide (NO) to form peroxynitrite (ONOO−). Peroxynitrite can react with other molecules, such as tyrosines, resulting in their nitration. Superoxide also reacts directly with macromolecules such as proteins and nucleic acids. The scavenging of superoxide typically occurs through superoxide dismutases of which there are 3 major types: intracellular (SOD-1 [Cu/Zn-SOD], mitochondrial [SOD-2 Mn-SOD], and extracellular [SOD-3]). Besides causing oxidative damage, superoxide has an important role as a signaling molecule. Cells use small molecules such as NO to activate or suppress various processes within the cell. Superoxide has been recognized for many years to be such a molecule. For example, it is known to initiate mitosis in certain cells (3). Over the last decade, our group demonstrated that superoxide plays a special role relevant to RGCs. Specifically, we showed that it signals the death of the cell body, or soma, when the axon is injured (4,5). In other words, injury to the axon of the RGC caused an increase in superoxide within its soma. This finding was accomplished by imaging superoxide using specialized fluorescent probes in rat retinas after optic nerve transection. The increase in superoxide could be seen a few days after axonal injury, followed a day later by death of the RGC. Using a variety of techniques, we established that the superoxide was not simply a result of the cell in the final throes of death but, rather, a signal that both preceded and was necessary for death. We did this by showing that other drugs that decrease the levels of superoxide (e.g., pegylated superoxide dismutase); both decreased the levels of superoxide and prevented the death of the RGC. Based on these studies, we concluded that superoxide was a signal for RGC death after axonal injury (5,6). SUPEROXIDE AND CECOCENTRAL SCOTOMAS How is superoxide relevant to optic neuropathies in which cecocentral scotomas occur? The next sections will discuss 3 specific optic neuropathies in turn, namely, LHON, the optic neuropathy associated with vitamin B12 deficiency and the toxic optic neuropathy caused by ethambutol. Each of these is associated with cecocentral scotomas, and for each of these, we have evidence that superoxide is generated at increased levels. Leber Hereditary Optic Neuropathy In at least 95% of patients with LHON, there is a mutation at 1 of 3 sites within the mitochondrial DNA (mtDNA). The most common is the 11778 mutation, followed by the 3460 and 14484 mutations. There is a slow-to-rapid development of loss of vision in 1 or both eyes. If only 1 eye is involved initially, the second eye follows within weeks to months. The loss of vision typically occurs in the late teens or early 20s, but it can occur at any age. There is a strong male predominance, which is as yet unexplained, especially as mtDNA is present in all cells (except mature erythrocytes) of both genders. All of the 3 primary mutations that produce LHON are contained in mtDNA coding for components of the complex I of the mitochondrial electron transport chain. Complex I serves as an NADH:ubiquinone oxidoreductase. In other words, NADH, a product of the Krebs cycle, is oxidized at the same time that ubiquinone, a molecule that carries electrons between complexes, is reduced. Functionally, 2 electrons are transported from NADH to ubiquinone at the same time that 4 protons (H+) are transported across the inner membrane of the mitochondria into the mitochondrial intermembrane space. This set of reactions has 2 results. First, electrons are transported to various loci in the electron transport chain. Second, protons are pumped across the inner membrane to form a voltage gradient. The voltage gradient, or electromotive potential, is the basis for another complex, complex V, to generate adenosine triphosphate (ATP) in the process of transferring protons back across the inner membrane into the mitochondrial matrix. For many years, it was assumed that the mechanism by which LHON mtDNA mutations in complex I caused visual loss was a deficiency of ATP, for example, by decreased pumping of protons or some other mechanism. This made sense, given that ATP is essential for cellular function, and RGCs, with their very long axons relative to the size of their somas, would presumably have high ATP demands. However, there are some flaws in this assumption, related to the fact that RGCs are specifically affected in LHON, whereas other cells are less commonly involved. We pointed out several years ago that diseases characterized by decreased ATP production from mutations in mtDNA usually are not associated with death of RGCs (7). Instead, they are associated with death of photoreceptors, as occurs in mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes (MELAS; mtDNA position 3243) or neuropathy, ataxia, and retinitis pigmentosa (NARP; mtDNA position 8993). Frequently, there is abnormal extraocular muscle function, as well as other systemic involvement such as abnormal cardiac conduction deficits and pancreatic dysfunction. Tissues such as photoreceptors and extraocular muscles are highly energy-consuming, and any disruption of ATP production in MELAS or NARP usually will affect patients early in the course of their disease. Therefore, if there were a deficiency in ATP production in LHON, there should be effects on photoreceptors and not, or at least not only, on RGCs. The second reason to suspect that ATP production is less relevant to LHON than previously believed is that studies of LHON cybrids demonstrate only a relatively small effect on ATP production. Cybrids are cells in which the mitochondria are from one cell source, usually having mutant mtDNA, whereas the rest of the cell is from another source, usually a wild-type dividing cell. This allows study of the specific effects of mtDNA mutations without affecting other aspects of cellular function. Surprisingly, the respiration deficits that would decrease ATP production are not particularly marked (8–12), although this is not always the case (13). Note that it is currently not possible to make cybrids from isolated RGCs because a dividing cell is necessary, and RGCs, like other neurons, do not divide. Superoxide is produced in LHON cybrids that are made in neuronal cell lines (14). For example, Wong and colleagues showed an approximate doubling of superoxide production in LHON 11778 or 3460 cybrids compared with control, nonmutant cybrids (14). They suggested that this effect was specific to differentiated neurons. However, they used a neuronal cell line that was different from RGCs, and thus, their findings would not the specific damage to RGCs in How do LHON mutations result in an increase in As the of complex I is as an NADH:ubiquinone oxidoreductase. If the of electrons to ubiquinone is complex I will the which can react with free oxygen to form In other words, the with the LHON mutations and their effects on complex I is less to decreased ATP but to an of superoxide from to electrons the electron transport to other in turn, in those electrons with molecular oxygen to form should an increase in superoxide in LHON to RGC death but not death of other are present in all cells in the mature and superoxide should be in those cells as The to RGCs is, The is that superoxide is not only a free radical that can react with other molecules to oxidative damage, but it also is a signaling molecule. As superoxide is a signal for RGC to after the axon is hypothesis is that the increased superoxide the of the RGC into that axon injury has although it has The RGC the process of by the superoxide and eventually Other cells in the may not use superoxide as a signal for cell death for this can be in a study of in which superoxide is resulting in the levels of superoxide within the cell being than have decreased of RGCs, with the to that superoxide levels in cells other than RGCs the RGCs to die, when there is axon injury and injury to the RGCs. In LHON a disease in which superoxide is produced because of mutations in complex I of the mitochondrial electron transport chain. RGCs may be specifically to increased superoxide because it is a signaling molecule for cell death after axon The increased superoxide would result in specific loss of RGCs, with relative of other cells within the and in the B12 Optic Neuropathy is a term used for the optic neuropathy that from of in in those on patients with various disorders or have resulting in of and in to decrease of vitamin In all the is an of vitamin from its in the or of in the Occasionally, abnormalities in or cell of vitamin B12 are There are of nutritional from a deficiency of other most commonly vitamin The clinical of vitamin B12 optic neuropathy is bilateral visual decreased color vision, cecocentral scotomas, and the of temporal disc sometimes with of the temporal disc. these disc features are similar to those seen in patients with B12 has several within of the and optic neuropathy. It is that most of these abnormalities are to its role as a for 2 and that its deficiency will result in increased levels of and In some vitamin B12 levels in the may be in the but there are levels of that there is a vitamin B12 deficiency the levels. The of vitamin B12 optic neuropathy is usually large of vitamin B12 through a followed by at a The form of vitamin B12 in is that is because of its the group on could be toxic to RGCs, or can free the and not in its of essential drugs B12 as a Superoxide As part of a with of the in we to as superoxide for RGC death after axon We molecules that and laboratory for We their role as and showed that some as superoxide in RGCs They also were in RGC death after optic nerve in We that the of and vitamin B12 were very with both having a Based on this we that vitamin B12 could as a superoxide A an from the laboratory of at showing that is a superoxide with approaching that of superoxide We on a of to the of vitamin in the form of to superoxide in RGCs and from cell death. our have been for the main findings are: In the vitamin B12 is an of superoxide produced by with Superoxide RGCs in cells used the cell line its is not an vitamin B12 superoxide produced in RGCs after axon transection. superoxide RGC death after optic nerve transection. for B12 Optic Neuropathy We that vitamin B12 in to its with to and a role as an superoxide in RGCs. deficiency would be specifically to RGCs as in the on LHON, RGCs use superoxide as an intracellular signaling molecule for after axon that superoxide is being generated within cells as part of the mitochondrial electron transport if superoxide is a signaling an RGC would of intracellular the superoxide might cell death. The superoxide within such as the various superoxide should be as they are for other that RGCs do not and be if they die, it is not that they would a for superoxide levels that is more than that of other We have suggested a role for vitamin B12 as an superoxide This is and will be to that this is a mechanism relevant to RGCs. It is very to optic neuropathy from vitamin B12 deficiency in and more than months of such deficiency does not an loss of RGCs. it is possible that vitamin B12 does not the same role in as it does in This is to other between and with to optic neuropathies, for example, given primarily a not an RGC is that are to other superoxide scavenging molecules within cells in to vitamin B12 this is an area of In these are with the hypothesis that vitamin B12 the known of nutritional optic neuropathy, is to an in superoxide scavenging and that levels of superoxide within RGCs would be for the bilateral visual loss associated with cecocentral scotomas that occurs from RGC death in this disease. Optic Neuropathy is commonly used to and other especially is the most common of toxic optic neuropathy and is characterized by bilateral loss of visual acuity, cecocentral scotomas, and optic disc In some there is a temporal of the visual field defect that sometimes the that the damage is primarily at or the optic This is different from the cecocentral scotoma associated with involvement of the papillomacular bundle. The for to produce an optic neuropathy its use in patients have visual the to this optic neuropathy and are that it is to will the optic neuropathy, how it can be RGCs are how to the visual loss other than by the In many of optic neuropathy, there is when the visual loss is However, the is with to or reverse the loss of studies demonstrated that of patients with optic neuropathy visual after was an high for the only known A there is specific reason to suspect that is associated with superoxide However, in that we have in we increased levels of superoxide after of using the of as a for superoxide In of Superoxide by by We rat RGCs by and on to a for and The cells were to 3 for 1 with in the last to superoxide reacts with superoxide to form which has specific and The cells were by fluorescent or with a fluorescent The of in a compared with that to superoxide generation and not generation of some other reactive oxygen species that might also some were with pegylated superoxide which cells and only superoxide and not other reactive oxygen This the that the an increase in superoxide The of these is that superoxide in rat RGCs. In of Superoxide by Using In eye of an of or 3 with concentration to The other eye was not and as were later with a using the for and a for with 3 demonstrated small but production of superoxide in cells within the RGC layer that were not fluorescent whereas induction was seen in with the or 1 of ethambutol. evidence of superoxide induction was seen in eyes. that can superoxide in RGCs and presumably to their death. Note that these used an acute to high of the to be to in to very high of in demonstrated and or not this is related to superoxide production is the mechanism for causing an increase in superoxide is currently but could be related to effects of and the of with complex I SUPEROXIDE CECOCENTRAL SCOTOMAS the if superoxide is a common pathophysiological for LHON, vitamin optic neuropathy, and optic neuropathy, this does not a cecocentral scotoma In other words, should the papillomacular bundle be and should axons or their RGCs in the be relatively The to the fact that the axons in the papillomacular bundle are than there is this there is strong evidence to that RGCs the papillomacular bundle are cells with small the axons are small for most of their course the disc, these features are different from fibers approaching the disc from other and colleagues have made that the size of RGC axons is relevant to the effects of a decrease in ATP production in the of LHON, with a between the ATP produced and the ATP in small large fibers of RGCs However, as in the on LHON, a in ATP production is to be the main in this and also in vitamin optic neuropathy or optic neuropathy. Instead, a process used by for small and large axons can be to the of superoxide as of the ATP for axon conduction is for the and at the of primarily after an has the axon and the axon as the 2 major associated with the of an axon The these by and to the extracellular and intracellular The of and is an and the of ATP being will be to the of which at the of the at the of Superoxide is a of ATP production in the mitochondrial electron transport and the of superoxide being produced will be to the of ATP to the that at the axon The of superoxide should be to the axon given that most superoxide is by intracellular superoxide The is in small fibers than in large fibers because the area is to the and the is to the of the that the of superoxide production is to and at the axon area and that the superoxide is to axon there will be relatively more superoxide production than in small fibers compared with large In other words, there should be a relatively between superoxide production to ATP used to axon and in small RGC axons than in large This would a involvement of small axons in the papillomacular bundle. However, as pointed out by it is not fiber size that would the damage in this It is possible that the of the axons in the retinal nerve fiber layer the temporal disc or the axons the disc that is the critical There are of optic neuropathy in which the visual field are of There is also a study in showing axon damage there are of LHON in which there is involvement based on or evidence findings are not directly explained by superoxide levels causing death of RGCs. possible reason for involvement of the chiasm is that the crossing fibers within the chiasm a small as they and each in the same that a the fibers as they each those the would be in those the chiasm is The of a fiber is than one with a more The of and with fibers also may be Other Optic Cecocentral This hypothesis 3 specific optic neuropathies, but there are other optic neuropathies, such as optic and optic neuropathy, in which the same clinical pattern The is highly and is only in the of optic is associated most with mutations in the and both of which are important for mitochondrial function. in have evidence that deficiency reactive oxygen species a variety of and is by superoxide It would not be if deficiency in patients with optic to increased superoxide levels in most with more in RGCs for the same reason that it occurs in is another in which there may be a role for is to which mitochondrial This to in the mitochondrial electron transport chain. The can react with molecular oxygen to form In in does not the RGC death that it does in but in primarily death Therefore, it is if studies in can to the mechanism by which an optic neuropathy. for of Optic Cecocentral the discussion, one might that drugs that superoxide levels within RGCs might be for any or all of these This is a assumption, but there are several The most important is that it is the of intracellular superoxide that is and a superoxide is to the it may not be It also has to the cell at high levels. For example, patients with high levels of vitamin B12 sense, but the intracellular concentration is at a high for the long it may not be a superoxide to be that our laboratory has such as pegylated superoxide and are but their use in would a development process. There has been in drugs such as in for A clinical was but did not its primary for vision loss in LHON However, of the from the were because it was a study was as a that would to as a ubiquinone electron However, studies show that also is a superoxide It may be because it intracellular superoxide and not because it mitochondrial transport in this one could or not drugs such as could be used in other optic neuropathies associated with cecocentral scotomas. I have a hypothesis that several optic neuropathies, all characterized by a similar clinical The hypothesis is on the of intracellular superoxide within RGCs as a common for the of cell death that The of the papillomacular bundle to have superoxide levels is to the size of the fibers a hypothesis that also the crossing fibers of the of this is and is an of several studies that have been to this hypothesis will be developed and its in both in I of my laboratory in the by the discussion, and I also for with many of my and

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