Inhibition of IκB Kinase-β Protects Dopamine Neurons Against Lipopolysaccharide-Induced Neurotoxicity

Abstract

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.

Redox Control of Microglial Function: Molecular Mechanisms and Functional Significance

“…Among those are IKKb and probably IKKe, which create phosphorylate-specific serines in the NF-jB inhibitor IjBa. This phosphorylation targets IjB for degradation through the ubiquitin/proteasome pathway, thus relieving NF-jB from this constrain, and enabling NF-jB stabilization and nuclear translocation (362). Other kinases that participate indirectly in phosphorylation of NF-jB isoforms or regulate NF-jB indirectly through the IKK pathway include the Mitogen-activated protein kinase/ERK kinase-1 (209), AKT (121), PKC (73,137,149), CK2 (122), and PKA (370).…”

Contributions of central and systemic inflammation to the pathophysiology of Parkinson's disease

“…Particularly, it prevented the activation of microglial oxidative pathways and the release of pro-inflammatory cytokines by specific blockade of the NF-κB signalling pathway (Zhang et al, 2010).…”

Neuroinflammation in the pathophysiology of Parkinson’s disease and therapeutic evidence of anti-inflammatory drugs

“…When NF-kB is activated, it enters the nucleus and stimulates the gene transcription of several proinflammatory factors including inducible nitric oxide synthase (iNOS), interleukin (IL)-1b, IL-6, cyclooxigenase 2 (COX-2) and tumor necrosis factor-a (TNF-a by the microglia 19,20 . Probably because of this, the proinflammatory cytokines IL-1b, TNF-a, IL-2 and IL-6 are expressed at higher levels in PD post-mortem brains as well as in cerebrospinal fluid (CSF) and serum of PD patients, compared with age-matched controls 5 .…”