TY - JOUR
T1 - Testing NF-kB-based therapy in hemiparkinsonian monkeys
AU - Mondal, Susanta
AU - Roy, Avik
AU - Jana, Arundhati
AU - Ghosh, Sankar
AU - Kordower, Jeffrey H.
AU - Pahan, Kalipada
N1 - Funding Information:
Acknowledgements This study was supported by grants from NIH (NS64564) and Michael J. Fox Foundation. The authors would like to thank Dr. Bichun Ouyang for statistical analysis.
PY - 2012/9
Y1 - 2012/9
N2 - 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-kB, a proinflammatory transcription factor, participates in the transcription of many proinflammatory molecules, this study evaluates the ability of a peptide corresponding to the NF-kB essential modifier (NEMO)-binding domain (NBD) of I?B kinase (IKK)a or IKKβ to protect dopaminergic neurons in hemiparkinsonian monkeys. First, we found that NF-kB 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-kB 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-kB-based therapy to PD clinics.
AB - 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-kB, a proinflammatory transcription factor, participates in the transcription of many proinflammatory molecules, this study evaluates the ability of a peptide corresponding to the NF-kB essential modifier (NEMO)-binding domain (NBD) of I?B kinase (IKK)a or IKKβ to protect dopaminergic neurons in hemiparkinsonian monkeys. First, we found that NF-kB 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-kB 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-kB-based therapy to PD clinics.
KW - Dopamine
KW - Dopaminergic neurons
KW - Monkey
KW - Motor function
KW - NF-kB
KW - Parkinson's disease
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U2 - 10.1007/s11481-012-9377-9
DO - 10.1007/s11481-012-9377-9
M3 - Article
C2 - 22661311
AN - SCOPUS:84866080814
SN - 1557-1890
VL - 7
SP - 544
EP - 556
JO - Journal of Neuroimmune Pharmacology
JF - Journal of Neuroimmune Pharmacology
IS - 3
ER -