TY - JOUR
T1 - Selective inhibition of NF-κB activation prevents dopaminergic neuronal loss in a mouse model of Parkinson's disease
AU - Ghosh, Anamitra
AU - Roy, Avik
AU - Liu, Xiaojuan
AU - Kordower, Jeffrey H.
AU - Mufson, Elliott J.
AU - Hartley, Dean M.
AU - Ghosh, Sankar
AU - Mosley, R. Lee
AU - Gendelman, Howard E.
AU - Pahan, Kalipada
PY - 2007/11/20
Y1 - 2007/11/20
N2 - Parkinson's disease (PD) is the second most common neurodegenerative disorder. Despite intense investigations, no effective therapy is available to stop its onset or halt its progression. The present study evaluates the ability of peptide corresponding to the NF-κB essential modifier-binding domain (NBD) of IκB kinase α(IKKα) or IKKβ to prevent nigrostriatal degeneration in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of PD and establish a role for NF-κB in human parkinsonism. First, we found that NF-κB was activated within the substantia nigra pars compacta of PD patients and MPTP-intoxicated mice. However, i.p. injection of wild-type NBD peptide reduced nigral activation of NF-κB, suppressed nigral microglial activation, protected both the nigrostriatal axis and neurotransmitters, and improved motor functions in MPTP-intoxicated mice. These findings were specific because mutated NBD peptide had no effect. We conclude that selective inhibition of NF-κB activation by NBD peptide may be of therapeutic benefit for PD patients.
AB - Parkinson's disease (PD) is the second most common neurodegenerative disorder. Despite intense investigations, no effective therapy is available to stop its onset or halt its progression. The present study evaluates the ability of peptide corresponding to the NF-κB essential modifier-binding domain (NBD) of IκB kinase α(IKKα) or IKKβ to prevent nigrostriatal degeneration in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of PD and establish a role for NF-κB in human parkinsonism. First, we found that NF-κB was activated within the substantia nigra pars compacta of PD patients and MPTP-intoxicated mice. However, i.p. injection of wild-type NBD peptide reduced nigral activation of NF-κB, suppressed nigral microglial activation, protected both the nigrostriatal axis and neurotransmitters, and improved motor functions in MPTP-intoxicated mice. These findings were specific because mutated NBD peptide had no effect. We conclude that selective inhibition of NF-κB activation by NBD peptide may be of therapeutic benefit for PD patients.
KW - MPTP
KW - NBD peptides
KW - Neurodegeneration
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U2 - 10.1073/pnas.0704908104
DO - 10.1073/pnas.0704908104
M3 - Article
C2 - 18000063
AN - SCOPUS:36749015082
SN - 0027-8424
VL - 104
SP - 18754
EP - 18759
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 47
ER -