Dawn Chin

Neuroprotective Properties of Curcumin in Alzheimer’s Disease – Merits and Limitations

As demographics in developed nations shift towards an aging population, neurodegenerative pathologies, especially dementias such as Alzheimers disease, pose one of the largest challenges to the modern health care system. Since there is yet no cure for dementia, there is great pressure to discover potential therapeutics for these diseases. One popular candidate is curcumin or diferuloylmethane, a polyphenolic compound that is the main curcuminoid found in Curcuma longa (family Zingiberaceae). In recent years, curcumin has been reported to possess anti-amyloidogenic, antiinflammatory, anti-oxidative, and metal chelating properties that may result in potential neuroprotective effects. Particularly, the hydrophobicity of the curcumin molecule hints at the possibility of blood-brain barrier penetration and accumulation in the brain. However, curcumin exhibits extremely low bioavailability, mainly due to its poor aqueous solubility, poor stability in solution, and rapid intestinal first-pass and hepatic metabolism. Despite the many efforts that are currently being made to improve the bioavailability of curcumin, brain concentration of curcumin remains low. Furthermore, although many have reported that curcumin possesses a relatively low toxicity profile, curcumin applied at high doses, which is not uncommon practice in many in vivo and clinical studies, may present certain dangers that in our opinion have not been addressed sufficiently. Herein, the neuroprotective potential of curcumin, with emphasis on Alzheimers disease, as well as its limitations will be discussed in detail.

Curcumin may impair iron status when fed to mice for six months

Curcumin has been shown to have many potentially health beneficial properties in vitro and in animal models with clinical studies on the toxicity of curcumin reporting no major side effects. However, curcumin may chelate dietary trace elements and could thus potentially exert adverse effects. Here, we investigated the effects of a 6 month dietary supplementation with 0.2% curcumin on iron, zinc, and copper status in C57BL/6J mice. Compared to non-supplemented control mice, we observed a significant reduction in iron, but not zinc and copper stores, in the liver and the spleen, as well as strongly suppressed liver hepcidin and ferritin expression in the curcumin-supplemented mice. The expression of the iron-importing transport proteins divalent metal transporter 1 and transferrin receptor 1 was induced, while hepatic and splenic inflammatory markers were not affected in the curcumin-fed mice. The mRNA expression of other putative target genes of curcumin, including the nuclear factor (erythroid-derived 2)-like 2 and haem oxygenase 1 did not differ between the groups. Most of the published animal trials with curcumin-feeding have not reported adverse effects on iron status or the spleen. However, it is possible that long-term curcumin supplementation and a Western-type diet may aggravate iron deficiency. Therefore, our findings show that further studies are needed to evaluate the effect of curcumin supplementation on iron status.

Resveratrol and Lifespan in Model Organisms

BACKGROUND Resveratrol may possess life-prolonging and health-benefitting properties, some of which may resemble the effect of caloric restriction (CR). CR appears to prolong the lifespan of model organisms in some studies and may benefit human health. However, for humans, restricting food intake for an extended period of time seems impracticable and substances imitating the beneficial effects of CR without having to reduce food intake could improve health in an aging and overweight population. METHODS We have reviewed the literature studying the influence of resveratrol on the lifespan of model organisms including yeast, flies, worms, and rodents. We summarize the in vivo findings, describe modulations of molecular targets and gene expression observed in vivo and in vitro, and discuss how these changes may contribute to lifespan extension. Data from clinical studies are summarized to provide an insight about the potential of resveratrol supplementation in humans. RESULTS Resveratrol supplementation has been shown to prolong lifespan in approximately 60% of the studies conducted in model organisms. However, current literature is contradictory, indicating that the lifespan effects of resveratrol vary strongly depending on the model organism. While worms and killifish seemed very responsive to resveratrol, resveratrol failed to affect lifespan in the majority of the studies conducted in flies and mice. Furthermore, factors such as dose, gender, genetic background and diet composition may contribute to the high variance in the observed effects. CONCLUSION It remains inconclusive whether resveratrol is indeed a CR mimetic and possesses life-prolonging properties. The limited bioavailability of resveratrol may further impede its potential effects.

Einleitung und Epidemiologie

Nach Angaben der Weltgesundheitsorganisation (World Health Organization, WHO) sind Krankheiten des Herz-Kreislauf-Systems weltweit fur etwa ein Drittel aller Todesfalle verantwortlich und stellen somit die haufigste Todesursache dar (WHO 2002). In Deutschland wurden fur das Jahr 2006 insgesamt ca. 360.000 Todesfalle durch Krankheiten des Kreislaufsystems verzeichnet (WHO 2004), was einem Anteil von etwa 45 % an der Gesamtmortalitat entspricht.

Bedeutung von Nahrungsfaktoren für die Gefäßgesundheit

In der Pravention von Herz-Kreislauf-Erkrankungen hat eine „gesunde“ Ernahrung einen besonderen Stellenwert und es gibt entsprechende Empfehlungen.

Stickstoffmonoxid-Synthasen (NOS) und deren Bedeutung in der Pathogenese kardiovaskulärer Erkrankungen

Die Stickstoffmonoxid-Synthasen (NOS) werden in die drei Isoformen unterteilt: endotheliale NOS (eNOS), induzierbare NOS (iNOS) und neuronale NOS (nNOS). Allen drei Formen ist die katalytische Umwandlung von L-Arginin zu L-Citrullin gemeinsam, bei der als Nebenprodukt Stickstoffmonoxid (NO) entsteht. Als Cosubstrate dieser Reaktion dienen reduziertes Nikotinamidadenindinukleotidphosphat (NADPH) und molekularer Sauerstoff. Zu den Redoxfaktoren der NO-Synthese zahlen Eisen-(II)-haltiges Ham, Tetrahydrobiopterin, Flavinmononukleotid (FMN), Flavinadenindinukleotid (FAD) und reduzierte Thiole.

Molekulare Mechanismen der Atherosklerose

Atherosklerose ist eine progressive Erkrankung, die durch Ansammlung und Ablagerung von Lipiden und extrazellularer Matrix in den Arterien charakterisiert ist und mit Prozessen der Oxidation und Inflammation einhergeht. Eine weit verbreitete Theorie bezuglich der Atherogenese ist die response to injury-Theorie, wonach eine endotheliale Schadigung und die daraus resultierende Dysfunktion des Endothels das primare Ereignis in der Entwicklung einer Atherosklerose darstellen. Die weiteren Veranderungen der arteriellen Gefaswande werden dabei als Antwort auf die initiale Schadigung des Endothels betrachtet.

Apolipoprotein E-Genotyp und Gefäßgesundheit

Apolipoprotein E (ApoE) wird zu etwa 60 % in der Leber synthetisiert, aber auch das Gehirn und Makrophagen zahlen zu den wichtigen Syntheseorten dieses Lipoproteins. Als eine Hauptkomponente der Lipoproteine ist ApoE wesentlich am Cholesterol- und Lipidtransport beteiligt und vermittelt dabei als Ligand die Bindung der Lipoproteine an Rezeptoren, vorwiegend an Rezeptoren der LDL-Rezeptor-Familie. Unabhangig von der Bedeutung im Lipoproteinstoffwechsel wurden weitere Funktionen des ApoE identifiziert. In den atherosklerotischen Plaques sind Monozyten in der Lage, nach einer Aktivierung signifikante Mengen von bis zu 20 % des gesamten ApoE zu bilden. Dieses induzierte ApoE vermittelt antiatherogene Effekte, lokal begrenzt auf die atherosklerotischen Plaques. Bisher konnte die Bedeutung des monozytaren ApoE noch nicht abschliesend geklart werden. Bekannt ist jedoch, dass ApoE hierbei als ein parakriner Mittler die Funktionen der Endothelzellen, glatten Muskelzellen, Lymphozyten und Makrophagen, und damit auch die Atherogenese, beeinflussen kann.