Pentoxyphylline and propentophylline are inhibitors of TNF-ot release in monocytes activated by advanced glycation endproducts

Non-enzymatic glycation of proteins with reducing sugars and subsequent transition metal-catalyzed oxidation leads to the formation of protein-bound "advanced glycation endproducts" (AGEs). They accumulate on long-lived protein deposits inducing senile plaques in Alzheimer's disease. AGE-modified proteins are able to activate microglia and astroglia and can cause chronic inflammation. The aim of the present study was to confirm the stimulatory effect of different AGEs on TNF-alpha release in human monocytes. Furthermore, the effects of four xanthine derivatives on AGE-induced TNF-alpha release were investigated. We show that chicken egg albumin-AGEs prepared with glucose and chicken egg albumin-AGEs prepared with methylglyoxal dose-dependently induce TNF-alpha release. The xanthine derivatives pentoxyphylline and propentophylline attenuate AGE-induced TNF-alpha release in a dose-dependent manner. Theophylline at low concentrations slightly stimulated TNF-alpha release whereas caffeine had no effect. The inhibition of the AGE-induced TNF-alpha release by pentoxyphylline and propentophylline provides interesting pharmacological strategies for diseases with local neuroinflammation such as Alzheimer's disease.