Selective inhibition of NF-kappaB activation prevents dopaminergic neuronal loss in a mouse model of Parkinson's disease.
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-kappaB essential modifier-binding domain (NBD) of IkappaB kinase alpha (IKKalpha) or IKKbeta 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-kappaB in human parkinsonism. First, we found that NF-kappaB 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-kappaB, 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-kappaB activation by NBD peptide may be of therapeutic benefit for PD patients.
Ghosh
Anamitra
A
Department of Neurological Sciences, Rush University Medical Center, Chicago, IL 60612, USA.
Roy
Avik
A
Liu
Xiaojuan
X
Kordower
Jeffrey H
JH
Mufson
Elliott J
EJ
Hartley
Dean M
DM
Ghosh
Sankar
S
Mosley
R Lee
RL
Gendelman
Howard E
HE
Pahan
Kalipada
K
D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / Q000494:pharmacology; D000818:Animals; D001665:Binding Sites; D004195:Disease Models, Animal; D018450:Disease Progression; D004298:Dopamine / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D008297:Male; D008636:Mesencephalon / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D009043:Motor Activity / Q000187:drug effects; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D010300:Parkinson Disease / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D010455:Peptides / Q000494:pharmacology
D016328:NF-kappa B; D010455:Peptides; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D004298:Dopamine