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Differential Recovery of Retinal Function After Mitochondrial Inhibition by Methanol Intoxication

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Differential Recovery of Retinal Function After Mitochondrial Inhibition by Methanol Intoxication Differential Recovery of Retinal Function after Mitochondrial Inhibition by Methanol Intoxication Marina T. Seme,1 Phyllis Summerfelt,2 Jay Neitz,2 Janis T. Eells,1 and Michele M. Henry1 PURPOSE. The authors’ laboratory has previously documented ally develop between 18 and 48 hours after methanol ingestion formate-induced retinal toxicity in a rodent model of methanol and range from mild photophobia and misty or blurred vision intoxication. These studies determined functional, bioener- to markedly reduced visual acuity and complete blindness. getic, and structural recovery of the retina after methanol Susceptibility among persons to the acute effects of methanol intoxication. is highly variable, and the minimum lethal dose is considered to 4–6 METHODS. Rats were intoxicated with methanol, and retinal be between 300 mg/kg and 1 g/kg. The minimum dose function was assessed by electroretinography 72 hours after causing permanent visual defects is unknown, although blind- the initial dose of methanol and after a 72-hour recovery pe- ness has been reported after ingestion of as little as 4 ml of 7,8 riod. Retinal energy metabolites, glutathione (GSH) concentra- methanol. tions, and histology were determined at the same time points. Methanol toxicity is primarily attributable to its metabolite, formic acid. Formic acid is the toxic metabolite responsible for RESULTS. Both rod-dominated and UV-cone–mediated electro- the metabolic acidosis and visual toxicity observed in human retinogram responses were profoundly attenuated in methanol- 5,6,9 intoxicated rats. In rats allowed to recover from methanol methanol poisoning. Formate has been hypothesized to produce retinal and optic nerve toxicity by disrupting mito- intoxication, there was significant, although incomplete, re- 10,11 covery of rod-dominated retinal function. However, there was chondrial energy production. In vitro studies have shown no demonstrable improvement in UV-cone–mediated re- that formate inhibits the activity of cytochrome oxidase, the sponses. Retinal adenosine triphosphate (ATP), adenosine terminal electron acceptor of the mitochondrial electron trans- port chain involved in adenosine triphosphate (ATP) synthe- diphosphate (ADP), and GSH concentrations were significantly 12,13 reduced after intoxication. Although retinal energy metabolites sis. Inhibition occurs subsequent to the binding of formic acid to the ferric heme iron in cytochrome oxidase, with returned to control values after the recovery period, retinal 12,13 GSH remained significantly depleted. Histopathologic changes inhibition constants between 5 and 30 mM. Permanent visual damage in methanol-intoxicated humans5 and nonhu- were apparent in the photoreceptors after methanol intoxica- 10,14 tion, with evidence of inner segment swelling and mitochon- man primates has been associated with prolonged expo- drial disruption. In animals allowed to recover from methanol sures (usually longer than 24 hours) to blood formate concen- intoxication, there was no evidence of histopathology at the trations in excess of 7 mM. However, very little information is light microscopic level; however, ultrastructural studies re- available on the potential for recovery of retinal function after vealed subtle photoreceptor mitochondrial alterations. toxic exposure to methanol-derived formate. Our laboratory has developed a rodent model of methanol CONCLUSIONS. These findings support the hypothesis that for- intoxication in which formate oxidation is selectively inhibited mate inhibits retinal mitochondrial function and increases ox- by treatment with nitrous oxide (N O). Subanesthetic concen- idative stress. They also provide evidence for a differential 2 trations of nitrous oxide inactivate the enzyme methionine sensitivity of photoreceptors to the cytotoxic actions of formic synthetase, reducing the production of tetrahydrofolate, a nec- acid, with a partial recovery of rod-dominated responses and 14–19 no recovery of UV-cone–mediated responses. (Invest Ophthal- essary cofactor for formate oxidation. This allows formate mol Vis Sci. 2001;42:834–841) to accumulate to toxic concentrations after methanol adminis- tration.14–19 In methanol-intoxicated rats, formic acidemia, metabolic acidosis, and visual toxicity develop, analogous to ethanol has been recognized as a human visual neuro- the toxicity seen in methanol intoxicated humans. Previous Mtoxin for more than a century, and the clinical features of studies in our laboratory have established this rodent model of acute human methanol toxicity have been extensively docu- 1–6 methanol-induced visual toxicity and have documented abnor- mented. Toxic exposure to methanol typically results in an malities in the flash-evoked visual potential and electroretino- initial transient central nervous system depression, followed by gram (ERG).16–19 an asymptomatic latent period lasting 12 to 24 hours. This The clinical features of methanol intoxication are remark- latent period is then followed by the development of formic ably similar to those of Leber’s hereditary optic neuropathy, acidemia, uncompensated metabolic acidosis, visual toxicity, nutritional amblyopia, and the recent Cuban epidemic of optic coma, and in extreme cases, death. Visual disturbances gener- neuropathy. In each case, there is evidence that a common pathophysiological mechanism involving mitochondrial dys- function contributes to the retinal and optic nerve dysfunction 20,21 From the 1Department of Pharmacology and Toxicology and the characteristic of the disease. We hypothesize that the ret- 2Department of Cell Biology, Neurobiology, and Anatomy, Medical inal pathophysiology of methanol intoxication is a conse- College of Wisconsin, Milwaukee. quence of formate-induced mitochondrial dysfunction. In this Supported in part by Grant ES06648 from the National Institute of study, we examined the effect of methanol intoxication on Environmental Health Sciences and by Grants EY01931 and EY11396 retinal function and retinal energy metabolism and assessed the from the National Eye Institute, National Institutes of Health. potential for recovery of retinal function after intoxication. Our Submitted for publication April 17, 2000; revised October 2, 2000; findings indicate that formate accumulation after methanol accepted October 26, 2000. Commercial relationships policy: N. intoxication inhibited retinal energy metabolism, increased ox- Corresponding author: Janis T. Eells, Department of Pharmacology idative stress in the retina, and profoundly attenuated retinal and Toxicology, Medical College of Wisconsin, 8701 Watertown Plank function. These studies also provide evidence for a complete Road, Milwaukee, WI 53226. [email protected] recovery of retinal energy metabolites and a partial recovery of Investigative Ophthalmology & Visual Science, March 2001, Vol. 42, No. 3 834 Copyright © Association for Research in Vision and Ophthalmology IOVS, March 2001, Vol. 42, No. 3 Retinal Recovery after Methanol Intoxication 835 retinal glutathione (GSH) and retinal function in animals al- on the lens to illuminate a 70° patch of retina in Maxwellian view. Light lowed to recover for 72 hours from methanol intoxication. calibrations were made with a silicon photodiode (PIN 10 DF; United Furthermore, our results are indicative of a differential sensi- Detector Technology, Hawthorne, CA). tivity of photoreceptors to the cytotoxic actions of formic acid ERG recordings were differentially amplified and computer aver- with a partial recovery of rod-dominated responses and no aged. The amplified signal was processed through a two-stage active recovery of UV-cone–mediated responses. narrow band-pass filter, the half voltage of which was 0.2 times the center frequency. To ensure that any transients in the response that METHODS occur at the onset of the stimulus pulses were not included in the average, the initiation of signal averaging was delayed by a preset Materials number of stimulus cycles (typically a minimum of 20). The resultant ERG is a noise-free, single-cycle, sinusoidal waveform. The averaged Methanol (high-performance liquid chromatography [HPLC] grade) was obtained from Sigma (St. Louis, MO). Thiobutabarbital (Inactin) responses were measured (peak-to-trough amplitude) from a calibrated 22 was purchased from Research Biochemicals (Natick, MA), atropine digital oscilloscope display. sulfate from AmVet (Fort Collins, CO), hydroxypropyl methylcellulose Before ERG analysis, ophthalmoscopic examination confirmed that (2.5%) drops from Iolab (Claremont, CA), and atropine sulfate ophthal- all eyes were free of lenticular opacities or other gross anomalies. Rats mic solution drops from Phoenix (St. Joseph, MO). All other chemicals were anesthetized with thiobutabarbital sodium (100 mg/kg, intraperi- were reagent grade or better. toneally), positioned in a stereotaxic apparatus (David Kopf, Tujunga, CA), and placed on a heating pad to maintain core body temperature Animals at 37°C. Atropine sulfate (0.05 mg/kg, subcutaneously) was adminis- Adult (250–350 g) male Long–Evans rats (Harlan Sprague–Dawley, tered to inhibit respiratory tract secretions. The pupil of the eye to be Madison, WI) were used throughout the experiments. Animals were tested was dilated by topical application of 1% atropine sulfate. Meth- supplied food and water ad libitum and maintained on a 12-hour ylcellulose was topically applied as a lubricant and to enhance electri- light–dark schedule in a temperature- and humidity-controlled envi- cal conduction. A circular, silver
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