In this study, we examined the effects of alpha lipoic acid treatment on streptozotocin (STZ)-induced diabetic rats and investigated the mechanisms underlying the protective action of alpha lipoic acid in diabetic retinal damage which was induced by inflammation and oxidative stress and activation of MAPKs and NF-kappa B signaling pathways. A total of 28 rats were divided into 4 groups: control, diabetes mellitus (45 mg/kg STZ, alpha lipoic acid (100 mg/kg/day, gavage, for 21 days) and diabetes mellitus+ alpha lipoic acid. We measured malondialdehyde, and reduced glutathione levels and superoxide dismutase and catalase activities, vascular endothelial growth factor, nitric oxide and prostaglandin E2 levels, inducible nitric oxide synthase and cyclooxygenase-2 mRNA levels and MAPK/NF-kappa B protein levels in retina tissue. Alpha lipoic acid enhances antioxidant enzyme activities and inhibits NF-kappa B activation and IKB-alpha degradation, phosphorylation of p38. ERK, and JNK proteins, the expression of inducible nitric oxide and cyclooxygenase-2 mRNA, and production of nitric oxide, vascular endothelial growth factor, and prostaglandin E2. These results suggest that the antioxidative and anti-inflammatory activities of alpha lipoic acid may be important mechanisms involved in the protective effect of alpha lipoic acid on diabetic retinal damage in STZ-induced diabetic rats. Furthermore. alpha lipoic acid markedly reduced retinal injury associated with diabetes, as demonstrated by reduced histological damage of retinal cells.