Discovery of Natural Products from Curcuma longa that Protect Cells from Beta-Amyloid Insult:  A Drug Discovery Effort against Alzheimer's Disease

Abstract

From Curcuma longa, two novel compounds, 4' '-(3' "-methoxy-4' "-hydroxyphenyl)-2' '-oxo-3' '-enebutanyl 3-(3'-methoxy-4'hydroxyphenyl)propenoate (calebin-A, 1) and 1,7-bis(4-hydroxy-3-methoxyphenyl)-1,4,6-heptatrien-3-one (2), and seven known compounds, 1,7-bis(4-hydroxy-3-methoxyphenyl)-1,6-heptadiene-3,5-dione (curcumin, 3), 1-(4-hydroxy-3-methoxyphenyl)-7-(4-hydroxyphenyl)-1,6-heptadiene-3,5-dione (demethoxycurcumin, 4), 1,7-bis(4-hydroxyphenyl)-1,6-heptadiene-3,5-dione (bisdemethoxycurcumin, 5), 1-hydroxy-1,7-bis(4-hydroxy-3-methoxyphenyl)-6-heptene-3,5-dione (6), 1,7-bis(4-hydroxyphenyl)-1-heptene-3,5-dione (7), 1,7-bis(4-hydroxyphenyl)-1,4,6-heptatrien-3-one (8), and 1,5-bis(4-hydroxy-3-methoxyphenyl)-1,4-pentadien-3-one (9), were isolated following a bioassay-guided fractionation scheme utilizing an assay to detect protection of PC12 cells from beta-amyloid insult. Compounds 1, 3-5, and 7 were found to more effectively protect PC12 cells from betaA insult (ED(50) = 0.5-10 microg/mL) than Congo red (10) (ED(50) = 37-39 microg/mL).

Curcumin Alters the Salt Bridge-containing Turn Region in Amyloid β(1–42) Aggregates

“…In vitro studies have shown that curcumin can retard the process of amyloid ␤ (A␤) aggregation (5,6), which is supposed to be the initiator of AD. It disrupts the formation of the long straight A␤ fibrils (5,7) and reduces A␤ toxicity (8,9). Moreover, it can also disrupt the preformed A␤ fibrils (6,7).…”

Protective Effect of Chlorogenic Acid against Aβ-Induced Neurotoxicity

“…The protection of PC12 cells from Aβ by chlorogenic acid was determined by measuring the potential of the cell to reduce MTT to MTT formazan, which indicates the cell viability (Park and Kim, 2002). Briefl y, exponentially growing PC12 cells (4×10 4 cells/well) were plated in 96-well tissue culture plates, after which the cells were pretreated with different concentrations of chlorogenic acid (1, 4, 20 and 100 μg/ml) for 1 h. As a vehicle control, cells were treated with 0.1% DMSO.…”

Small molecule inhibitors of Aβ‐aggregation and neurotoxicity

“…The common use of tumeric as a curry spice has pointed to its main constituent, curcumin, as a possible mediator of anti-Ab effects. Indeed, curcumin and related compounds like calebin-A, dimethoxycurcumin, and bidemethoxycurcumin, inhibit fibril formation and extension and promote destabilization of pre-aggregated Ab peptides [Kim et al, 2005;Ono et al, 2004;Park and Kim, 2002;Yang et al, 2005]. Examination of the structure-activity function of curcumin has identified three important molecular features, including a hydroxyl substitution on the aromatic end group, a narrow linker length between 8-16 Å , and the presence of a second terminal phenyl group that determines its anti-aggregant properties [Reinke and Gestwicki, 2007].…”

“…Examination of the structure-activity function of curcumin has identified three important molecular features, including a hydroxyl substitution on the aromatic end group, a narrow linker length between 8-16 Å , and the presence of a second terminal phenyl group that determines its anti-aggregant properties [Reinke and Gestwicki, 2007]. In vitro, curcumin protects against Ab-induced death of PC-12, SH-SY5Y neuroblastoma, and human umbilical vein endothelial cells, via anti-oxidant actions [Baum and Ng, 2004;Kim et al, 2001;Park and Kim, 2002;Yang et al, 2005]. Not surprisingly, intravenously-injected curcumin binds to parenchymal and vascular amyloid deposits in the brains of TgAPP swe / PS1 and Tg2576 mice [Garcia-Alloza et al, 2007;Yang et al, 2005].…”