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Neuroinflammation and angiogenesis contribute to classical neuronal mechanisms underpinning the pathophysiology of <jats:sc>l<\/jats:sc>\u2010dopa\u2010induced dyskinesia, a motor complication associated with <jats:sc>l<\/jats:sc>\u2010dopa therapy in Parkinson's disease. The efficacy of thalidomide and the more potent derivative 3,6\u2032\u2010dithiothalidomide on dyskinesia was tested in the 6\u2010hydroxydopamine Parkinson's disease model.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Three weeks after 6\u2010hydroxydopamine infusion, rats received 10 days of treatment with <jats:sc>l<\/jats:sc>\u2010dopa plus benserazide (6 mg\/kg each) and thalidomide (70 mg\/kg) or 3,6\u2032\u2010dithiothalidomide (56 mg\/kg), and dyskinesia and contralateral turning were recorded daily. Rats were euthanized 1 hour after the last <jats:sc>l<\/jats:sc>\u2010dopa injection, and levels of tumor necrosis factor\u2010\u03b1, interleukin\u201010, OX\u201042, vimentin, and vascular endothelial growth factor immunoreactivity were measured in their striatum and substantia nigra reticulata to evaluate neuroinflammation and angiogenesis. Striatal levels of GLUR1 were measured as a <jats:sc>l<\/jats:sc>\u2010dopa\u2010induced postsynaptic change that is under tumor necrosis factor\u2010\u03b1 control.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Thalidomide and 3,6\u2032\u2010dithiothalidomide significantly attenuated the severity of <jats:sc>l<\/jats:sc>\u2010dopa\u2010induced dyskinesia while not affecting contralateral turning. Moreover, both compounds inhibited the <jats:sc>l<\/jats:sc>\u2010dopa\u2010induced microgliosis and excessive tumor necrosis factor\u2010\u03b1 in the striatum and substantia nigra reticulata, while restoring physiological levels of the anti\u2010inflammatory cytokine interleukin\u201010. <jats:sc>l<\/jats:sc>\u2010Dopa\u2010induced angiogenesis was inhibited in both basal ganglia nuclei, and <jats:sc>l<\/jats:sc>\u2010dopa\u2010induced GLUR1 overexpression in the dorsolateral striatum was restored to normal levels.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>These data suggest that decreasing tumor necrosis factor\u2010\u03b1 levels may be useful to reduce the appearance of dyskinesia, and thalidomide, and more potent derivatives may provide an effective therapeutic approach to dyskinesia. \u00a9 2019 International Parkinson and Movement Disorder 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