Indomethacin has been suggested for the treatment of Alzheimer's disease (AD), but its use is limited by gastrointestinal and renal toxicity. To overcome this limitation, D-Pharm Ltd. (Rehovot, Israel) developed DP-155 (mixture of 1-steroyl and 1-palmitoyl-2-{6-[1-(p-chlorobenzoyl)-5-methoxy-2-methyl-3-indolyl acetamido] hexanoyl}-sn-glycero-3-phosophatidyl choline), a lecithin derivative of indomethacin. Safety was tested by daily oral administration of DP-155 or indomethacin to rats in a dose range of 0.007 to 0.28 mmol/kg. The prevalence of gastrointestinal ulceration was significantly lower (10-fold) for DP-155 than for indomethacin, and the ulcerations were delayed. Signs of renal toxicity, namely reduced urine output and increased urine N-acetyl glycosaminidase to creatinine ratio, were 5-fold lower for DP-155. Indomethacin, but not an equimolar dose of DP-155, reduced urine bicycloprostaglandin E 2 . An equimolar oral dose of DP-155 or indomethacin, administered every 4 h for 3 days, was equally efficacious in reducing the levels of A42 in the brains of Tg2576 mice. Indomethacin was the principal metabolite of DP-155 in the serum. After DP-155 oral administration, indomethacin's half-life in the serum and the brain was 22 and 93 h, respectively, compared with 10 and 24 h following indomethacin oral administration. The brain to serum ratio was 3.5 times higher for DP-155 than indomethacin. This finding explains the efficacy of DP-155 in reducing A42 brain levels, despite the low systemic blood concentrations of indomethacin derived from DP-155. In conclusion, compared with indomethacin, DP-155 has significantly lower toxicity in the gut and kidney while maintaining similar efficacy to indomethacin in lowering A42 in the brains of Tg2576 mice. This superior safety profile highlights DP-155's potential as an improved indomethacin-based therapy for AD.Indomethacin belongs to the nonsteroidal anti-inflammatory drug (NSAID) family. The use of NSAIDs was found to have an inverse correlation with the prevalence and severity of Alzheimer's disease (AD) in epidemiological and clinical studies (in t' Veld et al., 2001). Alzheimer's disease is characterized by three pathological hallmarks: extracellular amyloid  (A) plaques, intracellular neurofibrillary tangles (composed of hyperphosphorylated Tau protein), and neuronal and synaptic loss. The pathology development is accompanied by marked inflammatory processes (microglial and astrocytic reaction) (McGeer and McGeer, 1999). Indomethacin inhibits A plaque formation via ␥-secretase inhibition, which is a cyclooxygenase (COX)-independent process (Weggen et al., 2001). In addition, NSAIDs have COX-dependent anti-inflammatory and neuroprotective effects (Halliday et al., 2000;Weggen et al., 2001 ABBREVIATIONS: NSAID, nonsteroidal anti-inflammatory drug; AD, Alzheimer's disease; A, amyloid ; COX, cyclooxygenase; GI, gastrointestinal; PGE, prostaglandin E; GFR, glomerular filtration rate; DP-155, mixture of 1-steroyl and 1-palmitoyl-2-{6-[1-(p-chlorobenzoyl...
