Parkinson's disease (PD) is one of the most devastating neurodegenerative disorders in human. In spite of extensive research on the pathogenesis of PD, no effective therapy is available to halt this devastating neurodegenerative process. Recently we have demonstrated that Parkinsonian neurotoxin MPP+ induces the activation of NF-?B in human and mouse glial cells, that NF-?B activation is induced in vivo in the SNpc of PD patients and MPTP-intoxicated mice and that selective inhibition of NF-?B by NBD peptide results in significant protection of nigrostriatal neurons against MPTP-induced neurodegeneration in mice. These mice results suggest that this NF-?B-based therapeutic approach may be useful in PD. As we know mice results are not always translated to humans. Had all mice results been replicated in PD in human, the PD would have been cured long ago. Therefore, we would like to examine the efficacy of NEMO-binding domain peptides in inhibiting the disease process in a monkey model of PD, the best available model for human PD. First, we will investigate if this peptide enters into monkey brain. Second, activation of microglia and astroglia and production of proinflammatory molecules play an important role in the pathogenesis of several neurodegenerative disorders including PD. Our studies will indicate if NBD peptide treatment is capable of inhibiting the activation of microglia and astroglia and attenuating the expression of proinflammatory molecules in MPTP-intoxicated hemiparkinsonian monkeys. Third, it has been shown that nigrostriatal dopaminergic neurons in PD patients as well as in MPTP-intoxicated monkeys disappear. We will investigate if NBD peptide can protect these neurons in MPTP-intoxicated hemiparkinsonian monkeys. Fourth, this proposal will examine if NBD peptide can restore the level of dopamine in the striatum of MPTP-intoxicated monkeys. Fifth, similar to PD, MPTP intoxicated monkeys also display locomotor abnormalities. We will test if NBD peptide can improve locomotor activities in MPTP-intoxicated monkeys. If our mice results are replicated in monkeys, it could be a remarkable advancement in the treatment of PD. PHS 398/2590 (Rev. 11/07) Page Continuation Format Page

Public Health Relevance

In spite of extensive research on the pathogenesis of Parkinson's disease (PD), no effective therapy is available to halt this devastating neurodegenerative process. Here we would like to test the efficacy of NBD peptide, a specific inhibitor of induced NF-?B activation, in inhibiting the disease process in a monkey model of PD, the best available model for human PD. Results obtained from this proposal will increase the possibility of treating PD patients with NBD peptides as primary or adjunct therapy. PHS 398/2590 (Rev. 11/07) Page Continuation Format Page

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21NS064564-02
Application #
8084206
Study Section
Cell Death in Neurodegeneration Study Section (CDIN)
Program Officer
Sieber, Beth-Anne
Project Start
2010-06-15
Project End
2013-05-31
Budget Start
2011-06-01
Budget End
2013-05-31
Support Year
2
Fiscal Year
2011
Total Cost
$147,000
Indirect Cost
Name
Rush University Medical Center
Department
Neurosciences
Type
Schools of Medicine
DUNS #
068610245
City
Chicago
State
IL
Country
United States
Zip Code
60612
Chandra, Goutam; Rangasamy, Suresh B; Roy, Avik et al. (2016) Neutralization of RANTES and Eotaxin Prevents the Loss of Dopaminergic Neurons in a Mouse Model of Parkinson Disease. J Biol Chem 291:15267-81
Roy, A; Mondal, S; Kordower, J H et al. (2015) Attenuation of microglial RANTES by NEMO-binding domain peptide inhibits the infiltration of CD8(+) T cells in the nigra of hemiparkinsonian monkey. Neuroscience 302:36-46
Jana, Arundhati; Modi, Khushbu K; Roy, Avik et al. (2013) Up-regulation of neurotrophic factors by cinnamon and its metabolite sodium benzoate: therapeutic implications for neurodegenerative disorders. J Neuroimmune Pharmacol 8:739-55
Khasnavis, Saurabh; Ghosh, Anamitra; Roy, Avik et al. (2013) Castration induces Parkinson disease pathologies in young male mice via inducible nitric-oxide synthase. J Biol Chem 288:20843-55
Corbett, Grant T; Roy, Avik; Pahan, Kalipada (2013) Sodium phenylbutyrate enhances astrocytic neurotrophin synthesis via protein kinase C (PKC)-mediated activation of cAMP-response element-binding protein (CREB): implications for Alzheimer disease therapy. J Biol Chem 288:8299-312
Ghosh, Arunava; Pahan, Kalipada (2012) Gemfibrozil, a lipid-lowering drug, induces suppressor of cytokine signaling 3 in glial cells: implications for neurodegenerative disorders. J Biol Chem 287:27189-203
Roy, Avik; Ghosh, Anamitra; Jana, Arundhati et al. (2012) Sodium phenylbutyrate controls neuroinflammatory and antioxidant activities and protects dopaminergic neurons in mouse models of Parkinson's disease. PLoS One 7:e38113
Mondal, Susanta; Roy, Avik; Jana, Arundhati et al. (2012) Testing NF-?B-based therapy in hemiparkinsonian monkeys. J Neuroimmune Pharmacol 7:544-56
Corbett, Grant T; Roy, Avik; Pahan, Kalipada (2012) Gemfibrozil, a lipid-lowering drug, upregulates IL-1 receptor antagonist in mouse cortical neurons: implications for neuronal self-defense. J Immunol 189:1002-13
Khasnavis, Saurabh; Pahan, Kalipada (2012) Sodium benzoate, a metabolite of cinnamon and a food additive, upregulates neuroprotective Parkinson disease protein DJ-1 in astrocytes and neurons. J Neuroimmune Pharmacol 7:424-35

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