Parkinson's disease (PD) is a progressive neurological disorder characterized by a selective loss of dopamine (DA) neurons in the substantia nigra (SN). Although current therapy can control symptoms of this disorder, there is no effective therapy available to halt its progression. Recently, neuroinflammation has been recognized as an important contributor to the pathogenesis of PD, and nuclear factor-B (NF-B) plays a key role in regulating neuroinflammation. Hence, the modulation of NF-B pathway may have therapeutic potential for PD. Activation of NF-B depends on the phosphorylation of its inhibitor, IB, by the specific IB kinase (IKK) subunit IKK-. Compound A (7-[2- ,3]oxazin-2-one hydrochloride), a potent and selective inhibitor of IKK-, has recently been reported to provide cardioprotection through specific suppression of NF-B signaling. The present study, for the first time, elucidates neuroprotective effects of compound A. Daily subcutaneous injection of compound A (1 mg/kg) for 7 days inhibited the activation of microglia induced by nigral stereotaxic injection of lipopolysaccharide (LPS) and significantly attenuated LPS-induced loss of DA neurons in the SN. In vitro mechanistic studies revealed that neuroprotective effects of compound A were mediated by 1) suppressing the activity of microglial NADPH oxidase and decreasing the production of reactive oxygen species, and 2) inhibiting NF-B-mediated gene transcription of various proinflammatory mediators in microglia via IKK- suppression. These findings indicate that compound A afforded potent neuroprotection against LPS-induced neurodegeneration through selective inhibition of NF-B activation and may be of potential benefit in the treatment of PD.Parkinson's disease (PD) is the second most common neurodegenerative disorder, and it is characterized by a slow and progressive loss of dopamine (DA) neurons in the substantia nigra (SN) pars compacta of the ventral midbrain and the subsequent loss of DA content in the striatum. The cardinal clinical symptoms of PD include dyskinesia, resting tremor, rigidity, and gait disturbance. Current therapeutic interventions are limited to alleviating the symptoms of PD, and they fail to halt the progression of neurodegeneration (Gao et al., 2003a).Although oxidative stress, mitochondrial dysfunction, excitotoxicity, and apoptotic processes have been identified as being involved in neuronal degeneration (Nagatsu and Sawada, 2006), the mechanisms responsible for the progressive feature of neurodegeneration are not fully understood. In recent years, increasing evidence has strongly suggested that neuroinflammation is an important contributor to the pathogenesis of neurodegenerative diseases, such as PD, Alzheimer's disease, and multiple sclerosis.