Thalidomide-based TNF-α inhibitors for neurodegenerative diseases

Nigel H. Greig, Tony Giordano, Xiaoxiang Zhu, Qian Sheng Yu, Tracy Ann Perry, Harold W. Holloway, Arnold Brossi, Jack T. Rogers, Kumar Sambamurti, Debomoy K. Lahiri

Research output: Contribution to journalArticle

38 Scopus citations

Abstract

Inflammatory processes associated with the over-production of cytokines, particularly of TNF-α, accompany numerous neurodegenerative diseases, such as Alzheimer's disease, in addition to numerous systemic conditions, exemplified by rheumatoid arthritis and erythema nodosum leprosum (ENL). TNF-α has been validated as a drug target with Remicade and Enbrel available as prescription medications. Both, however, are large macromolecules, require injection and have limited brain access. The classical drug, thalidomide is being increasingly used in the clinical management of a wide spectrum of diseases. As its clinical value in treating ENL derives from its TNF-α inhibitory activity, thalidomide was chosen for structural modification for the discovery of novel and more potent isosteric analogues with appropriate lipophilicity to insure high brain penetration. TNF-α inhibitory activity was evaluated against lipopolysacharide (LPS) stimulated peripheral blood mononuclear cells (PBMC) in cell culture, whose viability was quantified to differentiate reductions in TNF-α secretion from that associated with cellular toxicity. Specific analogues potently inhibited TNF-α secretion, compared to thalidomide. This involved a post-transcriptional mechanism, as they decreased TNF-α mRNA stability via its 3′-untranslated region (UTR), as determined by luciferase activity in stably transfected cells with and without the 3′-UTR of human TNF-α.

Original languageEnglish (US)
Pages (from-to)1-9
Number of pages9
JournalActa Neurobiologiae Experimentalis
Volume64
Issue number1
StatePublished - Apr 20 2004

Keywords

  • Alzheimer's disease
  • Amyloid precursor protein
  • Amyloid-β peptide
  • Erythema nodosum leprosum (ENL)
  • Lipopolysacharide (LPS)
  • Peripheral blood mononuclear cells (PBMC)
  • Rheumatoid arthritis
  • Thalidomide
  • Thalidomide analogues
  • TNF-α inhibitors

ASJC Scopus subject areas

  • Neuroscience(all)

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    Greig, N. H., Giordano, T., Zhu, X., Yu, Q. S., Perry, T. A., Holloway, H. W., Brossi, A., Rogers, J. T., Sambamurti, K., & Lahiri, D. K. (2004). Thalidomide-based TNF-α inhibitors for neurodegenerative diseases. Acta Neurobiologiae Experimentalis, 64(1), 1-9.