Inflammation plays an important role in the pathogenesis of several neurodegenerative diseases, including Parkinson's disease. Recent reports have indicated that andrographolide (ANDRO) has an anti-inflammatory effect by modulating macrophage and neutrophil activity. Whereas microglia, the counterpart of macrophages in the brain, are pivotal in the inflammatory process in the central nervous system, the effect of ANDRO on inflammation-mediated neurodegeneration has not been examined. In this study, we show that both pretreatment and post-treatment with ANDRO exhibited a significant protective effect against lipopolysaccharide (LPS)-induced neurotoxicity in mixed neuron-glia cultures, as determined by [(3)H]dopamine uptake and immunocytochemical analysis. In contrast, ANDRO showed no protective effect on 1-methyl-4-phenyl-pyridine (0.5 microM)-induced neurotoxicity in neuron-enriched cultures. ANDRO significantly attenuated LPS-induced microglial activation and production of reactive oxygen species, tumor necrosis factor-alpha, nitric oxide, and prostaglandin E(2). Furthermore, ANDRO dose-dependently attenuated LPS-induced inducible nitric-oxide synthase and cyclooxygenase-2 protein expression in BV-2 microglia, as determined by Western blot. These findings demonstrate that ANDRO reduces inflammation-mediated dopaminergic neurodegeneration in mesencephalic neuron-glia cultures by inhibiting microglial activation. In addition, these results indicate that ANDRO may have clinical utility for the treatment of inflammation-related neurodegenerative disorders such as Parkinson's disease.