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Inhibition of IkappaB kinase-beta protects dopamine neurons against lipopolysaccharide-induced neurotoxicity.
J Pharmacol Exp Ther. 2010 Jun; 333(3):822-33.JP

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-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.

Authors+Show Affiliations

Neuropharmacology Section, Laboratory of Toxicology and Pharmacology, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina 27709, USA.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, N.I.H., Intramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

20190013

Citation

Zhang, Feng, et al. "Inhibition of IkappaB Kinase-beta Protects Dopamine Neurons Against Lipopolysaccharide-induced Neurotoxicity." The Journal of Pharmacology and Experimental Therapeutics, vol. 333, no. 3, 2010, pp. 822-33.
Zhang F, Qian L, Flood PM, et al. Inhibition of IkappaB kinase-beta protects dopamine neurons against lipopolysaccharide-induced neurotoxicity. J Pharmacol Exp Ther. 2010;333(3):822-33.
Zhang, F., Qian, L., Flood, P. M., Shi, J. S., Hong, J. S., & Gao, H. M. (2010). Inhibition of IkappaB kinase-beta protects dopamine neurons against lipopolysaccharide-induced neurotoxicity. The Journal of Pharmacology and Experimental Therapeutics, 333(3), 822-33. https://doi.org/10.1124/jpet.110.165829
Zhang F, et al. Inhibition of IkappaB Kinase-beta Protects Dopamine Neurons Against Lipopolysaccharide-induced Neurotoxicity. J Pharmacol Exp Ther. 2010;333(3):822-33. PubMed PMID: 20190013.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Inhibition of IkappaB kinase-beta protects dopamine neurons against lipopolysaccharide-induced neurotoxicity. AU - Zhang,Feng, AU - Qian,Li, AU - Flood,Patrick M, AU - Shi,Jing-Shan, AU - Hong,Jau-Shyong, AU - Gao,Hui-Ming, Y1 - 2010/02/26/ PY - 2010/3/2/entrez PY - 2010/3/2/pubmed PY - 2010/6/12/medline SP - 822 EP - 33 JF - The Journal of pharmacology and experimental therapeutics JO - J Pharmacol Exp Ther VL - 333 IS - 3 N2 - 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. SN - 1521-0103 UR - https://www.unboundmedicine.com/medline/citation/20190013/Inhibition_of_IkappaB_kinase_beta_protects_dopamine_neurons_against_lipopolysaccharide_induced_neurotoxicity_ L2 - https://jpet.aspetjournals.org/cgi/pmidlookup?view=long&pmid=20190013 DB - PRIME DP - Unbound Medicine ER -