Department of Oral Pathology, Medicine and Radiology Works

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Browsing Department of Oral Pathology, Medicine and Radiology Works by Subject "Alzheimer's disease"

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    Nuclear factor-kappa B: Glucocorticoid-induced leucine zipper interface analogs suppress pathology in an Alzheimer's disease model
    (Elsevier, 2018-01-01) Srinivasan, Mythily; Lahiri, Niloy; Thyagarajan, Anish; Witek, Emily; Hickman, Debra; Lahiri, Debomoy K.; Oral Pathology, Medicine and Radiology, School of Dentistry
    Introduction Glucocorticoid-induced leucine zipper is a regulatory protein that sequesters activated nuclear factor-kappa B p65. Previously, we showed that rationally designed analogs of the p65-binding domain of glucocorticoid-induced leucine zipper, referred to as glucocorticoid-induced leucine zipper analogs (GAs), inhibited amyloid β–induced metabolic activity and inflammatory cytokines in mixed brain cell cultures. Here, we investigate the therapeutic efficacy of GA in an Alzheimer's disease model. Methods GA and control peptides were synthesized covalently as peptide amides with the cell-penetrating agent. C57Bl/6J mice induced with lipopolysaccharide-mediated neuroinflammation (250 mg/kg i.p/day for six days) were treated on alternate days with GA-1, GA-2, or control peptides (25 mg/kg i.v). Brain tissues were assessed for gliosis, cytokines, and antiapoptotic factors. Results The brain tissues of GA-1– and GA-2–treated mice exhibited significantly reduced gliosis, suppressed inflammatory cytokines, and elevated antiapoptotic factors. Discussion The antineuroinflammatory effects of GA suggest potential therapeutic application for Alzheimer's disease.
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    Significance of NF-κΒ as a pivotal therapeutic target in the neurodegenerative pathologies of Alzheimer’s disease and multiple sclerosis
    (Taylor and Francis, 2015-04) Srinivasan, Mythily; Lahiri, Debomoy K.; Department of Oral Pathology, Medicine and Radiology, Indiana University School of Dentistry
    Introduction: Advances in molecular pathogenesis suggest that the chronic inflammation is a shared mechanism in the initiation and progression of multiple neurodegenerative diseases with diverse clinical manifestations such as Alzheimer’s disease (AD) and Multiple sclerosis (MS). Restricted cell renewal and regenerative capacity make the neural tissues extremely vulnerable to the uncontrolled inflammatory process leading to irreversible tissue damage. Areas covered: A predominant consequence of increased inflammatory signaling is the upregulation of the transcription factor, NF-κB with subsequent neuroprotective or deleterious effects depending on the strength of the signal and the type of NF-κB dimers activated. We discuss the interplay between neuroinflammation and neurodegeneration keeping in focus NF-κB signaling as the point of convergence of multiple pathways associated with the development of the neurodegenerative pathologies, AD and MS. Expert opinion: Considerable interest exists in developing efficient NF-κB inhibitors for neurodegenerative diseases. The review includes an overview of natural compounds and rationally designed agents that inhibit NF-κB and mediate neuroprotection in AD and MS. The key chemical moieties of the natural and the synthetic compounds provide efficient leads for the development of effective small molecule inhibitors that selectively target NF-κB activation; this would result in the desired benefit to risk therapeutic effects.