Testing NF-κB-based Therapy in Hemiparkinsonian Monkeys

Department of Neurological Sciences, Rush University Medical Center, 1735 West Harrison St, Suite 320, Chicago, IL 60612, USA.
Journal of Neuroimmune Pharmacology (Impact Factor: 4.11). 06/2012; 7(3):544-56. DOI: 10.1007/s11481-012-9377-9
Source: PubMed


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.

Download full-text


Available from: Avik Roy, Oct 09, 2015
17 Reads
  • Source
    • "Therefore, after intraperitoneal injection, NBD peptide entered into the CNS, reduced nigral activation of NF-κB, suppressed nigral expression of proinflammatory molecules, and attenuated nigrostriatal degeneration in MPTP-intoxicated mice. Similarly, after intramuscular injection, NBD peptide entered into the CNS and protected the nigrostriatum in hemiparkinsonian monkeys [38]. Peptides are generally costly. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Alzheimer’s disease (AD) is the most common form of dementia. Despite intense investigations, no effective therapy is available to halt its progression. We found that NF-κ B was activated within the hippocampus and cortex of AD subjects and that activated forms of NF-κ B negatively correlated with cognitive function monitored by Mini-Mental State Examination and global cognitive z score. Accordingly, NF-κ B activation was also observed in the hippocampus of a transgenic (5XFAD) mouse model of AD. It has been shown that peptides corresponding to the NF-κ B essential modifier (NEMO)-binding domain (NBD) of Iκ B kinase α (IKKα ) or Iκ B kinase β (IKKβ) specifically inhibit the induction of NF-κ B activation without inhibiting the basal NF-κ B activity. Interestingly, after intranasal administration, wild-type NBD peptide entered into the hippocampus, reduced hippocampal activation of NF-κ B, suppressed hippocampal microglial activation, lowered the burden of Aβ in the hippocampus, attenuated apoptosis of hippocampal neurons, protected plasticity-related molecules, and improved memory and learning in 5XFAD mice. Mutated NBD peptide had no such protective effect, indicating the specificity of our finding. These results suggest that selective targeting of NF-κ B activation by intranasal administration of NBD peptide may be of therapeutic benefit for AD patients.
    Journal of Alzheimer's disease: JAD 09/2015; 47(2):385-402. DOI:10.3233/JAD-150040 · 4.15 Impact Factor
  • Source
    • "The samples were mounted and observed under an Olympus IX81 fluorescent microscope. For tissue staining, brains were kept in 4% paraformaldehyde and 30-µm slices were sectioned in a cryostat followed by immunostaining as described before [28], [29]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Alzheimer's disease (AD), the leading cause of dementia in the aging population, is characterized by the presence of neuritic plaques, neurofibrillary tangles and extensive neuronal apoptosis. Neuritic plaques are mainly composed of aggregates of amyloid-β (Aβ) protein while neurofibrillary tangles are composed of the hyperphosphorylated tau protein. Despite intense investigations, no effective therapy is currently available to halt the progression of this disease. Here, we have undertaken a novel approach to attenuate apoptosis and tau phosphorylation in cultured neuronal cells and in a transgenic animal model of AD. RNS60 is a 0.9% saline solution containing oxygenated nanobubbles that is generated by subjecting normal saline to Taylor-Couette-Poiseuille (TCP) flow under elevated oxygen pressure. In our experiments, fibrillar Aβ1-42, but not the reverse peptide Aβ42-1, induced apoptosis and cell death in human SHSY5Y neuronal cells. RNS60, but not NS (normal saline), RNS10.3 (TCP-modified saline without excess oxygen) or PNS60 (saline containing excess oxygen without TCP modification), attenuated Aβ(1-42)-induced cell death. RNS60 inhibited neuronal cell death via activation of the type 1A phosphatidylinositol-3 (PI-3) kinase - Akt - BAD pathway. Furthermore, RNS60 also decreased Aβ(1-42)-induced tau phosphorylation via (PI-3 kinase - Akt)-mediated inhibition of GSK-3β. Similarly, RNS60 treatment suppressed neuronal apoptosis, attenuated Tau phosphorylation, inhibited glial activation, and reduced the burden of Aβ in the hippocampus and protected memory and learning in 5XFAD transgenic mouse model of AD. Therefore, RNS60 may be a promising pharmaceutical candidate in halting or delaying the progression of AD.
    PLoS ONE 08/2014; 9(8):e103606. DOI:10.1371/journal.pone.0103606 · 3.23 Impact Factor
  • Source
    • "Immunofluorescence analysis was performed as described earlier [25], [26], [27]. Briefly, cells cultured in 8-well chamber slides (Lab-Tek II) were fixed with 4% paraformaldehyde for 20 min followed by treatment with cold ethanol (−20°C) for 5 min and 2 rinses in PBS. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Increase of the density of dendritic spines and enhancement of synaptic transmission through ionotropic glutamate receptors are important events, leading to synaptic plasticity and eventually hippocampus-dependent spatial learning and memory formation. Here we have undertaken an innovative approach to upregulate hippocampal plasticity. RNS60 is a 0.9% saline solution containing charge-stabilized nanobubbles that are generated by subjecting normal saline to Taylor-Couette-Poiseuille (TCP) flow under elevated oxygen pressure. RNS60, but not NS (normal saline), PNS60 (saline containing a comparable level of oxygen without the TCP modification), or RNS10.3 (TCP-modified normal saline without excess oxygen), stimulated morphological plasticity and synaptic transmission via NMDA- and AMPA-sensitive calcium influx in cultured mouse hippocampal neurons. Using mRNA-based targeted gene array, real-time PCR, immunoblot, and immunofluorescence analyses, we further demonstrate that RNS60 stimulated the expression of many plasticity-associated genes in cultured hippocampal neurons. Activation of type IA, but not type IB, phosphatidylinositol-3 (PI-3) kinase by RNS60 together with abrogation of RNS60-mediated upregulation of plasticity-related proteins (NR2A and GluR1) and increase in spine density, neuronal size, and calcium influx by LY294002, a specific inhibitor of PI-3 kinase, suggest that RNS60 upregulates hippocampal plasticity via activation of PI-3 kinase. Finally, in the 5XFAD transgenic model of Alzheimer's disease (AD), RNS60 treatment upregulated expression of plasticity-related proteins PSD95 and NR2A and increased AMPA- and NMDA-dependent hippocampal calcium influx. These results describe a novel property of RNS60 in stimulating hippocampal plasticity, which may help AD and other dementias.
    PLoS ONE 07/2014; 9(7):e101883. DOI:10.1371/journal.pone.0101883 · 3.23 Impact Factor
Show more