Antineuroinflammatory Effect of NF-κB Essential Modifier-Binding Domain Peptides in the Adoptive Transfer Model of Experimental Allergic Encephalomyelitis

Abstract

It has been shown that peptides corresponding to the NF-κB essential modifier-binding domain (NBD) of IκB kinase α or IκB kinase β specifically inhibit the induction of NF-κB activation without inhibiting the basal NF-κB activity. The present study demonstrates the effectiveness of NBD peptides in inhibiting the disease process in adoptively transferred experimental allergic encephalomyelitis (EAE), an animal model of multiple sclerosis. Clinical symptoms of EAE were much lower in mice receiving wild-type (wt)NBD peptides compared with those receiving mutated (m)NBD peptides. Histological and immunocytochemical analysis showed that wtNBD peptides inhibited EAE-induced spinal cord mononuclear cell invasion and normalized p65 (the RelA subunit of NF-κB) expression within the spinal cord. Analysis of lymph node cells isolated from donor and recipient mice showed that wtNBD peptides but not mNBD peptides were able to shift the immune response from a Th1 to a Th2 profile. Consistently, wtNBD peptides but not mNBD peptides inhibited the encephalitogenicity of myelin basic protein-specific T cells. Furthermore, i.p. injection of wtNBD peptides but not mNBD peptides was also able to reduce LPS- and IFN-γ-induced expression of inducible NO synthase, IL-1β, and TNF-α in vivo in the cerebellum. Taken together, our results support the conclusion that NBD peptides are antineuroinflammatory, and that NBD peptides may have therapeutic effect in neuroinflammatory disorders such as multiple sclerosis.

Selective inhibition of NF-κB activation prevents dopaminergic neuronal loss in a mouse model of Parkinson's disease

“…Ghosh and colleagues (14) have used Antennapedia homeodomain to make NBD peptides cell permeable. However, our current results in the animal model of PD and our earlier results in the animal model of MS (32) suggest that Antennapedia homeodomain may be used to send peptides across the BBB.…”

“…Peptides usually do not enter into the CNS, and, therefore, sending peptides across the BBB is an important area of research. Earlier, we demonstrated anti-neuroinflammatory and protective effect of NBD peptide in experimental allergic encephalomyelitis, an animal model of multiple sclerosis (MS) (32). Here, we present evidence that this peptide enters into the CNS, reduces nigral activation of NF-B, suppresses nigral expression of proinflammatory molecules, and attenuates nigrostriatal degeneration in MPTP-intoxicated mice.…”

Activation of Peroxisome Proliferator-activated Receptor α Induces Lysosomal Biogenesis in Brain Cells

“…Sections were made from different brain regions, and for immunofluorescence staining on fresh frozen sections, anti-mouse TFEB (1:500), anti-mouse LAMP2 (1:200), and anti-mouse NeuN (1:500) were used. The samples were mounted and observed under Olympus BX41 fluorescence microscope (30).…”

Lipopolysaccharide (LPS)-stimulated iNOS Induction Is Increased by Glucosamine under Normal Glucose Conditions but Is Inhibited by Glucosamine under High Glucose Conditions in Macrophage Cells

“…Activation of macrophages or microglia by LPS stimulates mitogen-activated protein (MAP) kinases and NF-B. MAP kinases and NF-B are both strongly implicated in the regulation of iNOS expression by LPS (17)(18)(19)(20). NF-B is normally sequestered in the cytoplasm by inhibitors of NF-B, inhibitor of B (IB) proteins including IB␣ and IB␤.…”