Diabetic retinopathy (DR) is a hyperglycemia-induced ischemic disorder characterized by microvascular dysfunction and neovascularization. It is a leading cause of blindness in many countries, yet efficient drugs are limited now for prevention and treatment of DR. Low molecular weight fucoidan (LMWF), extract from brown algae, has been shown to possess multiple biological activities like anti-inflammation, anti-oxidation and anti-aggregation, which all could be beneficial for attenuating ischemia-induced tissue damages. Here, by comparing with calcium dobesilate, the potent antioxidant compound currently used for the treatment of DR, we investigated the protective effect of LMWF against DR in streptozotocin-induced diabetic mice and high glucose-promoted vascular endothelial growth factor (VEGF) production and cell proliferation in microvascular endothelial cells. One week after diabetes induction, the mice were administered with LMWF (50, 100 or 200 mg/kg/day) or calcium dobesilate (200 mg/kg/day) for four months, then the retinal pathological changes and neovascularization were detected by hematoxylin-eosin staining and fluorescein dextran angiography, respectively. Immunofluorescence staining, ELISA and RT-PCR were used to examine the expression levels of hypoxia-inducible factor-1 alpha (HIF-1 alpha) and VEGF in retina and endothelial cells. Here, we found that LMWF resembled calcium dobesilate, in alleviating retinal pathological change and hindering neovascularization due to diabetes in vivo. The relative levels of VEGF expression and HIF-1 alpha induction were also less in retinas of LMWF- or calcium dobesilate-treated diabetic mice than those in retinas of control mice. Furthermore, high glucose-induced VEGF overexpression and cell proliferation in primary cultured vascular endothelial cells were also inhibited by LMWF in a dose-dependent manner. Therefore, this study demonstrated that LMWF alleviates diabetic retinal neovascularization and damage likely through lowering HIF-1 alpha and VEGF expressions, providing a potential candidate drug for prevention and treatment of diabetic retinopathy. (C) 2013 Elsevier Ltd. All rights reserved.