Formate-induced inhibition of photoreceptor function in methanol intoxication

Formic acid is the toxic metabolite responsible for the retinal and optic n erve toxicity produced in methanol intoxication. Previous studies in our la boratory have documented formate-induced retinal dysfunction and histopatho logy in a rodent model of methanol intoxication. The present studies define the time and concentration dependence of formate-induced retinal toxicity in methanol-intoxicated rats. Retinal function was assessed 24, 48, and 72 h after the initial dose of methanol by flicker electroretinographic measur ements. Retinal histopathology was assessed at the same time intervals. Rod - and cone-mediated electroretinogram (ERG) responses were attenuated in a formate concentration- and time-dependent manner, and both retinal sensitiv ity and maximal responsiveness to light were diminished. Attenuation of UV- cone-mediated responses was temporally delayed in comparison to the functio nal deficits observed in the 15 Hz/510 nm responses, which have a rod-media ted component and occurred at significantly higher formate concentrations. Both 15 Hz/510 nm and UV-cone-mediated ERG responses were undetectable by 7 2 h; however, if light intensity was increased, a retinal ERG response coul d be recorded, indicating that photoreceptor function was profoundly attenu ated, but not abolished, under these intoxication conditions. Functional ch anges preceded structural alterations. Histopathological changes were most pronounced in the outer retina with evidence of inner segment swelling, pho toreceptor mitochondrial disruption, and the appearance of fragmented photo receptor nuclei in the outer nuclear layer. The nature of both the function al and structural alterations observed are consistent with formate-induced inhibition of mitochondrial energy production, resulting in photoreceptor d ysfunction and pathology.