Differential recovery of retinal function after mitochondrial inhibition by methanol intoxication.
OBJECTIVE
The authors' laboratory has previously documented formate-induced retinal toxicity in a rodent model of methanol intoxication. These studies determined functional, bioenergetic, and structural recovery of the retina after methanol intoxication.


METHODS
Rats were intoxicated with methanol, and retinal function was assessed by electroretinography 72 hours after the initial dose of methanol and after a 72-hour recovery period. Retinal energy metabolites, glutathione (GSH) concentrations, and histology were determined at the same time points.


RESULTS
Both rod-dominated and UV-cone-mediated electroretinogram responses were profoundly attenuated in methanol-intoxicated rats. In rats allowed to recover from methanol intoxication, there was significant, although incomplete, recovery of rod-dominated retinal function. However, there was no demonstrable improvement in UV-cone-mediated responses. Retinal adenosine triphosphate (ATP), adenosine diphosphate (ADP), and GSH concentrations were significantly reduced after intoxication. Although retinal energy metabolites returned to control values after the recovery period, retinal GSH remained significantly depleted. Histopathologic changes were apparent in the photoreceptors after methanol intoxication, with evidence of inner segment swelling and mitochondrial disruption. In animals allowed to recover from methanol intoxication, there was no evidence of histopathology at the light microscopic level; however, ultrastructural studies revealed subtle photoreceptor mitochondrial alterations.


CONCLUSIONS
These findings support the hypothesis that formate inhibits retinal mitochondrial function and increases oxidative stress. They also provide evidence for a differential sensitivity of photoreceptors to the cytotoxic actions of formic acid, with a partial recovery of rod-dominated responses and no recovery of UV-cone-mediated responses.
Department of Pharmacology and Toxicology, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226, USA.
M T
MT
Seme
P
P
Summerfelt
J
J
Neitz
J T
JT
Eells
M M
MM
Henry
D000244:Adenosine Diphosphate / Q000378:metabolism; D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D004596:Electroretinography; D005561:Formates / Q000378:metabolism; D005978:Glutathione / Q000378:metabolism; D008297:Male; D000432:Methanol / Q000633:toxicity*; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism; D051381:Rats; D020318:Rats, Long-Evans; D012160:Retina / Q000187:drug effects / Q000378:metabolism / Q000473:pathology / Q000502:physiology*
D005561:Formates; C030544:formic acid; D000244:Adenosine Diphosphate; D000255:Adenosine Triphosphate; D005978:Glutathione; D000432:Methanol