Neuroprotective and Antiinflammatory Properties of a Novel Demethylated Curcuminoid

Abstract

A demethylated derivative of curcumin (DC; 67.8% bisdemethylcurcumin, 20.7% demethylmonodemethoxycurcumin, 5.86% bisdemethoxycurcumin, 2.58% demethylcurcumin) was prepared by using a 95% extract of curcumin (C₉₅; 72.2% curcumin, 18.8% monodemethoxycurcumin, 4.5% bisdemethoxycurcumin). DC increased glutathione and reduced reactive oxygen species (ROS) in HT4 neuronal cells. In a model of glutamate-induced death of HT4, DC was more effective than C₉₅ in neuroprotection. The protective effects of DC were retained even when DC was withdrawn from culture media after pretreatment. DC treatment, unlike an equal dose of C₉₅, completely spared glutamate-induced loss of cellular GSH. Both DC and C₉₅ prevented glutamate-induced elevation of cellular ROS but failed to attenuate glutamate-induced elevation of intracellular calcium. In human microvascular endothelial cells (HMECs) challenged with TNF-α, GeneChip analysis revealed that only a subcluster of 23 TNF-α–inducible genes were uniquely sensitive to C₉₅. In sharp contrast, 1,065 TNF-α–inducible genes were sensitive to DC but not to C₉₅, suggesting that DC was more effective in antagonizing the effects of TNF-α on HMECs. Functional analysis identified that the genes uniquely sensitive to DC belonged in four functional categories: cytokine-receptor interaction, focal adhesion, cell adhesion, and apoptosis. Real-time PCR as well as ELISA studies demonstrated that TNF-α–inducible CXCL10 and CXCL11 expression was sensitive to DC but not to C₉₅. Flow-cytometry studies recognized ICAM-1 and VCAM-1 as TNF-α–inducible adhesion molecules that were uniquely sensitive to DC. Taken together, DC exhibited promising neuroprotective and antiinflammatory properties that must be characterized in vivo. Antioxid. Redox Signal. 11, 449–468.