title: Aspirin at low-intermediate concentrations protects retinal vessels in experimental diabetic retinopathy through non-platelet-mediated effects.
abstract: The prevention of diabetic retinopathy requires drugs that leverage the benefits of glycemic control without adding the burden of side effects. Aspirin at dosages of 1-1.5 g/day has prevented manifestations of diabetic retinal microangiopathy in a clinical trial as well as in studies with dogs. Because lower and safer doses of aspirin could be used if its beneficial effects on retinopathy were due to antithrombotic effects, we compared the effects of a selective antiplatelet drug (clopidogrel) to those of aspirin in streptozotocin-induced diabetic rats. Clopidogrel did not prevent neuronal apoptosis, glial reactivity, capillary cell apoptosis, or acellular capillaries in the retina of diabetic rats. Aspirin, at doses yielding serum levels (<0.6 mmol/l) well below the anti-inflammatory range for humans, prevented apoptosis of capillary cells and the development of acellular capillaries but did not prevent neuroglial abnormalities. The aldose reductase inhibitor sorbinil, used as the benchmark for the effect of the other drugs, prevented all abnormalities. The diabetic rat retina showed increased expression of the transcription factor CCAAT/enhancer-binding protein-beta, one of the known targets of low-intermediate concentrations of aspirin. Thus we found a spectrum of drug efficacy on the prevention of experimental diabetic retinopathy, ranging from the absent effect of a selective antiplatelet drug to the prevention of all abnormalities by an aldose reductase inhibitor. Aspirin at low-intermediate concentrations selectively prevented microangiopathy. The minimal effective dose of aspirin should now be sought.
authors.affiliation: Schepens Eye Research Institute and Department of Ophthalmology, Harvard Medical School, 20 Staniford St., Boston, Massachusetts 02114, USA.
authors.forename: Wei
authors.initials: W
authors.lastname: Sun
authors.forename: Chiara
authors.initials: C
authors.lastname: Gerhardinger
authors.forename: Zeina
authors.initials: Z
authors.lastname: Dagher
authors.forename: Todd
authors.initials: T
authors.lastname: Hoehn
authors.forename: Mara
authors.initials: M
authors.lastname: Lorenzi
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D001241:Aspirin / Q000627:therapeutic use*; D001792:Blood Platelets / Q000502:physiology; D000077144:Clopidogrel; D003921:Diabetes Mellitus, Experimental / Q000503:physiopathology*; D003930:Diabetic Retinopathy / Q000188:drug therapy*; D015232:Dinoprostone / Q000378:metabolism; D006801:Humans; D009474:Neurons / Q000187:drug effects / Q000473:pathology / Q000502:physiology; D010975:Platelet Aggregation Inhibitors / Q000627:therapeutic use; D051381:Rats; D012160:Retina / Q000378:metabolism; D012171:Retinal Vessels / Q000187:drug effects / Q000503:physiopathology*; D013988:Ticlopidine / Q000031:analogs & derivatives / Q000627:therapeutic use
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D010975:Platelet Aggregation Inhibitors; D000077144:Clopidogrel; D015232:Dinoprostone; D013988:Ticlopidine; D001241:Aspirin