Thalidomide-based TNF-alfa inhibitors for neurodegenerative diseases

Inflammatory processes associated with the over-production of cytokines, particularly of TNF-alfa, accompany numerous neurodegenerative diseases, such as Alzheimerʹs disease, in addition to numerous systemic conditions, exemplified by rheumatoid arthritis and erythema nodosum leprosum (ENL). TNF-alfa 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-alfa 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-alfa 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-alfa secretion from that associated with cellular toxicity. Specific analogues potently inhibited TNF-alfa secretion, compared to thalidomide. This involved a post-transcriptional mechanism, as they decreased TNF-alfa mRNA stability via its 3ʹ-untranslated region (UTR), as determined by luciferase activity in stably transfected cells with and without the 3ʹ-UTR of human TNF-alfa.