Inhibition of IkappaB kinase-beta protects dopamine neurons against lipopolysaccharide-induced neurotoxicity.
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-kappaB (NF-kappaB) plays a key role in regulating neuroinflammation. Hence, the modulation of NF-kappaB pathway may have therapeutic potential for PD. Activation of NF-kappaB depends on the phosphorylation of its inhibitor, IkappaB, by the specific IkappaB kinase (IKK) subunit IKK-beta. Compound A (7-[2-(cyclopropylmethoxy)-6-hydroxyphenyl]-5-[(3S)-3-piperidinyl]-1, 4-dihydro-2H-pyrido[2,3-d][1,3]oxazin-2-one hydrochloride), a potent and selective inhibitor of IKK-beta, has recently been reported to provide cardioprotection through specific suppression of NF-kappaB 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-kappaB-mediated gene transcription of various proinflammatory mediators in microglia via IKK-beta suppression. These findings indicate that compound A afforded potent neuroprotection against LPS-induced neurodegeneration through selective inhibition of NF-kappaB activation and may be of potential benefit in the treatment of PD.
Zhang
Feng
F
Neuropharmacology Section, Laboratory of Toxicology and Pharmacology, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina 27709, USA.
Qian
Li
L
Flood
Patrick M
PM
Shi
Jing-Shan
JS
Hong
Jau-Shyong
JS
Gao
Hui-Ming
HM
D000818:Animals; D001253:Astrocytes / Q000187:drug effects; D015153:Blotting, Western; D002478:Cells, Cultured; D004298:Dopamine / Q000378:metabolism / Q000502:physiology*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D051550:I-kappa B Kinase / Q000037:antagonists & inhibitors*; D007150:Immunohistochemistry; D007202:Indicators and Reagents; D053583:Interleukin-1beta / Q000378:metabolism; D008070:Lipopolysaccharides / Q000037:antagonists & inhibitors* / Q000633:toxicity*; D008297:Male; D017628:Microglia / Q000187:drug effects; D019255:NADPH Oxidases / Q000037:antagonists & inhibitors; D009457:Neuroglia / Q000187:drug effects; D009474:Neurons / Q000187:drug effects*; D018696:Neuroprotective Agents; D009498:Neurotoxins / Q000037:antagonists & inhibitors*; D009573:Nitrites / Q000378:metabolism; D010078:Oxazines / Q000494:pharmacology*; D011725:Pyridines / Q000494:pharmacology*; D051381:Rats; D011916:Rats, Inbred F344; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013481:Superoxides / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
C502972:7-(2-(cyclopropylmethoxy)-6-hydroxyphenyl)-5-(3-piperidinyl)-1,4-dihydro-2H-pyrido(2,3-d)(1,3)oxazin-2-one; D004791:Enzyme Inhibitors; D007202:Indicators and Reagents; D053583:Interleukin-1beta; D008070:Lipopolysaccharides; D018696:Neuroprotective Agents; D009498:Neurotoxins; D009573:Nitrites; D010078:Oxazines; D011725:Pyridines; D014409:Tumor Necrosis Factor-alpha; D013481:Superoxides; D019255:NADPH Oxidases; D051550:I-kappa B Kinase; D004298:Dopamine