DP-155, a lecithin derivative of indomethacin, is a novel nonsteroidal antiinflammatory drug for analgesia and Alzheimer's disease therapy

Abstract

DP-155 is a lipid prodrug of indomethacin that comprises the latter conjugated to lecithin at position sn-2 via a 5-carbon length linker. It is cleaved by phospholipase A2 (PLA)(2) to a greater extent than similar compounds with linkers of 2, 3, and 4 carbons. Indomethacin is the principal metabolite of DP-155 in rat serum and, after DP-155 oral administration, the half-life of the metabolite was 22 and 93 h in serum and brain, respectively, compared to 10 and 24 h following indomethacin administration. The brain to serum ratio was 3.5 times higher for DP-155 than for indomethacin. In vitro studies demonstrated that DP-155 is a selective cyclooxygenase (COX)-2 inhibitor. After it is cleaved, its indomethacin derivative nonselectively inhibits both COX-1 and -2. DP-155 showed a better toxicity profile probably due to the sustained, low serum levels and reduced maximal concentration of its indomethacin metabolite. DP-155 did not produce gastric toxicity at the highest acute dose tested (0.28 mmol/kg), while indomethacin caused gastric ulcers at a dose 33-fold lower. Furthermore, after repeated oral dosing, gastrointestinal and renal toxicity was lower (10- and 5-fold, respectively) and delayed with DP-155 compared to indomethacin. In addition to reduced toxicity, DP-155 had similar ameliorative effects to indomethacin in antipyretic and analgesia models. Moreover, DP-155 and indomethacin were equally efficacious in reducing levels of amyloid ss (Ass)42 in transgenic Alzheimer's disease mouse (Tg2576) brains as well as reducing Ass42 intracellular uptake, neurodegeneration, and inflammation in an in vitro AD model. The relatively high brain levels of indomethacin after DP-155 administration explain the equal efficacy of DP-155 despite its low systemic blood concentrations. Compared to indomethacin, the favored safety profile and equal efficacy of DP-155 establish the compound as a potential candidate for chronic use to treat AD-related pathology and for analgesia.

Figure 1

Chemical structure of DP‐155 and its parent compound, indomethacin.

Figure 2

(A) Effects of DP‐155 and indomethacin (IND) on the area of enhanced Aß uptake (top panel) and its accompanying microglial response, as assessed with ED1 immunostaining (bottom panel). Data expressed as a percentage of the Aß42 + RGD group mean (denoted by the dashed line) ± standard error of the mean. *P < 0.05; **P < 0.005. (B,C) Photomicrographs showing the effect of DP‐155 on neurodegeneration, as assessed with Fluoro‐Jade B staining in CA1 region of cultured hippocampal slices. (B) Treating with Aß and RGD caused marked increases in degenerating neurons. (C) This increase was reduced by about half with DP‐155 at 80 μM. Scale bar = 50 μm.

Figure 3

Analgesic effect of 0.01 mmol/kg DP‐155 or indomethacin, 2, 4, 6, and 8 h after oral administration, on the number of writhing episodes in a model of acute visceral pain induced by intraperitoneal injection of 0.06% acetic acid (0.1 mL/10g). (A) represents acetic acid; (V) represents vehicle; (I) represents indomethacin, and (D) represents DP‐155. Data presented as mean ± standard error. Asterisk denotes significance at P < 0.05.

Figure 4

Effect of DP‐155 and indomethacin (0.03 mmol/kg) on body temperature after induction of pyrexia. Data presented as mean ± standard error of the mean.