Efficacy of treatment after measurable diabeticlike retinopathy in galactose-fed rats.
OBJECTIVE
To determine whether the diabeticlike retinal microangiopathies of the galactose-fed rat model could be ameliorated if intervention by withdrawal of the galactose diet or treatment with the aldose reductase inhibitor AL-3152 was initiated after quantifiable microangiopathies had occurred.


METHODS
Weanling male Sprague-Dawley rats were randomized into five groups and fed for up to 24 months Purina laboratory chow (#5001) plus 50% starch (control [CON]), 50% D-galactose (galactose [GAL]), 50% D-galactose with AL-3152 (approximately 14 mg/kg per day) (prevention [PRV]), 50% D-galactose for 6 months followed by intervention with the inhibitor (intervention [INT]), or 50% D-galactose for 6 months followed by replacement with the 50% starch diet (withdrawal [GWD]). In rats on experimental diets and killed after 6, 18, and 24 months, one retina was prepared for transmission electron microscopy; the other was used for vessel wholemounts using elastase digestion. Capillary images were analyzed by computer morphometry.


RESULTS
At 6 months, the GAL rats exhibited statistically significant (P < 0.05) increases over CON rats in mean capillary basement membrane thickness, capillary density, and dilated channels. These parameters tended to increase with time in most groups, and the differences between GAL and age-matched CON rats were maintained at the 18- and 24-month endpoints. Although the microangiopathies were ameliorated by AL-3152 treatment from the onset (PRV), intervention after 6 months of galactosemia with either galactose withdrawal (GWD) or addition of inhibitor (INT) showed amelioration in only some parameters at 18 months and no statistically significant benefit at the 24-month endpoint.


CONCLUSIONS
Amelioration of galactose-induced retinal microangiopathies with AL-3152 in the prevention group suggests an efficacious application of aldose reductase inhibitors in treating diabetic retinopathy, provided treatment can begin soon after the onset of diabetes. Intervention after some of the earliest microscopic lesions neither halted progression of the angiopathy nor provided appreciable benefit at the 24-month follow-up.
Robison
W G
WG
National Eye Institute, National Institutes of Health, Bethesda, Maryland 20892-2740, USA.
Laver
N M
NM
Jacot
J L
JL
Chandler
M L
ML
York
B M
BM
Glover
J P
JP
D000449:Aldehyde Reductase / Q000037:antagonists & inhibitors; D000818:Animals; D003930:Diabetic Retinopathy / Q000139:chemically induced* / Q000178:diet therapy / Q000628:therapy*; D004032:Diet; D004791:Enzyme Inhibitors / Q000627:therapeutic use; D005449:Fluorenes / Q000627:therapeutic use; D005690:Galactose / Q000008:administration & dosage; D006827:Hydantoins / Q000627:therapeutic use; D007091:Image Processing, Computer-Assisted; D008297:Male; D008854:Microscopy, Electron; D051381:Rats; D017207:Rats, Sprague-Dawley; D012016:Reference Values; D012160:Retina / Q000648:ultrastructure; D012171:Retinal Vessels / Q000473:pathology
D004791:Enzyme Inhibitors; D005449:Fluorenes; D006827:Hydantoins; C076003:AL 3152; D000449:Aldehyde Reductase; D005690:Galactose