Role of glycogen synthase kinase-3 in l-DOPA-induced neurotoxicity

l-DOPA is the gold standard for the treatment of Parkinson's disease. Despite the obvious benefits of l-DOPA treatment, a potential drawback of such a treatment is its potential for neurotoxicity. The best-known potential mechanisms of l-DOPA toxicity involve oxidative stress, including nitrosative stress and increased generation of neurotoxins, oxidation of l-DOPA to quinone and semiquinone, mitochondrial dysfunction and genomic DNA damage. On the other hand, it has also been reported that l-DOPA is not neurotoxic, but rather neuroprotective. Although there are many studies on the neurotoxicity of l-DOPA, a debate regarding its effect on neuronal cells still remains. Glycogen synthase kinase-3 (GSK-3) affects a diverse range of biological functions controlling gene expression, cellular architecture and apoptosis. Recently, important roles of GSK-3 in l-DOPA neurotoxicity have been suggested by studies using an endoplasmic reticulum-stressed Parkinson's disease model. In this review, we focus our discussion on the following topics: i) l-DOPA neurotoxicity; ii) the role of GSK-3 in neuronal cell death; iii) the role of GSK-3 in l-DOPA neurotoxicity; and iv) the development of new GSK-3 inhibitors.