Testing NF-κB-based therapy in hemiparkinsonian monkeys.
Parkinson's disease (PD) is the most common human neurodegenerative disorder affecting movement, balance, flexibility, and coordination. Despite intense investigation, no effective therapy is available to stop the onset PD or halt its progression. The primate model of PD is considered to be one of the best available models for human PD. Since neuroinflammation plays an important role in the pathogenesis of PD and NF-κB, a proinflammatory transcription factor, participates in the transcription of many proinflammatory molecules, this study evaluates the ability of a peptide corresponding to the NF-κB essential modifier (NEMO)-binding domain (NBD) of IκB kinase (IKK)α or IKKβ to protect dopaminergic neurons in hemiparkinsonian monkeys. First, we found that NF-κB was activated within the substantia nigra pars compacta of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-intoxicated hemiparkinsonian monkeys. However, intramuscular injection of wild type NBD (wtNBD) peptide reduced nigral activation of NF-κB and expression of inducible nitric oxide synthase, protected both the nigrostriatal axis and neurotransmitters, and improved motor functions in hemiparkinsonian monkeys. These findings were specific as mutated NBD peptide did not exhibit such effects. These results may help in the translation of NF-κB-based therapy to PD clinics.
Department of Neurological Sciences, Rush University Medical Center, 1735 West Harrison St, Suite 320, Chicago, IL 60612, USA.
Susanta
S
Mondal
Avik
A
Roy
Arundhati
A
Jana
Sankar
S
Ghosh
Jeffrey H
JH
Kordower
Kalipada
K
Pahan
D000595:Amino Acid Sequence; D000818:Animals; D005260:Female; D051550:I-kappa B Kinase / Q000235:genetics / Q000378:metabolism; D008253:Macaca mulatta; D008969:Molecular Sequence Data; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D020734:Parkinsonian Disorders / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism*; D010455:Peptides / Q000235:genetics / Q000378:metabolism / Q000627:therapeutic use*; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism
C491731:IKBKG protein, human; C467063:NBD peptide, mouse; D016328:NF-kappa B; D010455:Peptides; D014409:Tumor Necrosis Factor-alpha; D051550:I-kappa B Kinase