curcumin and Niemann-Pick-Disease--Type-C

Curcumin, a hydrophobic polyphenol found in the rhizome of Curcuma longa, has been shown to reduce intracellular lipid accumulation in mouse models of lysosomal storage diseases such as Niemann-Pick type C. Exosomes are small extracellular vesicles secreted by cells in response to changes in intracellular ceramide composition. Curcumin can induce exosome/microvesicle release in cellular models of lipid deposition; however, the mechanism by which curcumin stimulates this release is unknown. In a model of lipid trafficking impairment in C6 glia cells, we show that curcumin stimulated ceramide synthesis by increasing the intracellular concentration of ceramide-dihydroceramide. Ceramide overload increased exosome/microvesicle secretion 10-fold, thereby reducing the concentration of lipids in the endolysosomal compartment. These effects were blocked by inhibitors of serine palmitoyltransferase (myriocin) and ceramide synthase (fumonisin B1). It is concluded that the decrease in intracellular lipid deposition induced by curcumin is mediated by increased ceramide synthesis and exosome/microvesicle release. This action may represent an additional health benefit of curcumin.

Topics: Animals; Cell Line, Tumor; Cell-Derived Microparticles; Ceramides; Curcumin; Exosomes; Fatty Acids, Monounsaturated; Fumonisins; Humans; Lipid Metabolism; Lipoproteins, LDL; Lysosomes; Neuroglia; Niemann-Pick Disease, Type C; Oxidoreductases; Rats; Serine C-Palmitoyltransferase

Niemann-Pick disease type C (NPC) is a neurodegenerative lysosomal storage disorder characterised by the storage of multiple lipids, reduced lysosomal calcium levels, impaired late endosome:lysosome fusion and neuroinflammation. NPC is caused by mutations in either of the two genes, NPC1 or NPC2, which are believed to function in a common cellular pathway, the function of which remains unclear. The complexity of the pathogenic cascade in NPC disease provides a number of potential clinical intervention points. To date, drugs that target pivotal stages in the pathogenic cascade have been tested as monotherapies or in combination with a second agent, showing additive or synergistic benefit. In this study, we have investigated whether we can achieve greater therapeutic benefit in the Npc1(-/-) mouse by combining three therapies that each targets unique aspects of the pathogenic cascade.. We have treated Npc1(-/-) mice with miglustat that targets sphingolipid synthesis and storage, curcumin that compensates for the lysosomal calcium defect by elevating cytosolic calcium, and the non-steroidal anti-inflammatory drug ibuprofen to reduce central nervous system inflammation.. We have found that triple combination therapy has a greater neuroprotective benefit compared with single and dual therapies, increasing the time period that Npc1(-/-) mice maintained body weight and motor function and maximally delaying the onset of Purkinje cell loss. In addition, ibuprofen selectively reduced microglial activation, while curcumin had no anti-inflammatory effects, indicating differential mechanisms of action for these two therapies. When taken together, these results demonstrate that targeting multiple unique steps in the pathogenic cascade maximises the clinical benefit in a mouse model of NPC1 disease.

Topics: 1-Deoxynojirimycin; Animals; Cerebellum; Curcumin; Drug Therapy, Combination; Ibuprofen; Intracellular Signaling Peptides and Proteins; Mice; Mice, Inbred BALB C; Mice, Knockout; Neuroprotective Agents; Niemann-Pick C1 Protein; Niemann-Pick Disease, Type C; Proteins

In order to determine the efficacy of curcumin in ameliorating symptoms of neurodegeneration in the mouse model of Niemann-Pick C1, a variety of formulations and dosages of curcumin, one comparable to one previously reported as efficacious, were provided orally to Npc1(-/-)mice. Plasma levels of curcumin, survival, tests of motor performance, and memory (in some cases) were performed. We found variable, but mild, increases in survival (1.5% to 18%). The greatest increased survival occurred with the highest dose (which was unformulated) while the control for the lipidated formulation (containing phosphatidylcholine and stearic acid) had an equivalent impact and other formulations, while not significantly increased, are also not statistically different in effect from the highest dose. We conclude that curcumin is not a highly efficacious treatment for neurodegeneration in Npc1(-/-) mice. Phosphatidylcholine and stearic acid should be studied further.

Topics: Aging; Animals; Avoidance Learning; Carrier Proteins; Chromatography, High Pressure Liquid; Curcumin; Diet; Intracellular Signaling Peptides and Proteins; Lipids; Mass Spectrometry; Membrane Glycoproteins; Memory; Mice; Mice, Inbred BALB C; Mice, Knockout; Motor Activity; Nerve Degeneration; Niemann-Pick C1 Protein; Niemann-Pick Disease, Type C; Pharmaceutical Vehicles; Phosphatidylcholines; Polymerase Chain Reaction; Postural Balance; Stearic Acids; Survival

Niemann-Pick type C1 (NPC1) disease is a neurodegenerative lysosomal storage disorder caused by mutations in the acidic compartment (which we define as the late endosome and the lysosome) protein, NPC1. The function of NPC1 is unknown, but when it is dysfunctional, sphingosine, glycosphingolipids, sphingomyelin and cholesterol accumulate. We have found that NPC1-mutant cells have a large reduction in the acidic compartment calcium store compared to wild-type cells. Chelating luminal endocytic calcium in normal cells with high-affinity Rhod-dextran induced an NPC disease cellular phenotype. In a drug-induced NPC disease cellular model, sphingosine storage in the acidic compartment led to calcium depletion in these organelles, which then resulted in cholesterol, sphingomyelin and glycosphingolipid storage in these compartments. Sphingosine storage is therefore an initiating factor in NPC1 disease pathogenesis that causes altered calcium homeostasis, leading to the secondary storage of sphingolipids and cholesterol. This unique calcium phenotype represents a new target for therapeutic intervention, as elevation of cytosolic calcium with curcumin normalized NPC1 disease cellular phenotypes and prolonged survival of the NPC1 mouse.

Topics: Acids; Animals; Calcium; Carrier Proteins; Cell Line; Cholesterol; Curcumin; Glycosphingolipids; Homeostasis; Humans; Intracellular Signaling Peptides and Proteins; Lysosomes; Membrane Glycoproteins; Mice; Mice, Knockout; Mutation; Niemann-Pick C1 Protein; Niemann-Pick Disease, Type C; Phenotype; Proteins; Sphingosine