Alzheimer's Disease Research - Completed Award
Wolfgang Quitschke, Ph.D.
State University of New York at Stony Brook
Stony Brook, NY
Title: Effect Of Serum-Solubilized Curcumin On Plaques In Alzheimer's Disease Transgenic Mice
Non-Technical Title: Effect Of Injectable Derivatives Of The Turmeric Spice On Plaques In AD Transgenic Mice
Duration: April 1, 2009 - March 31, 2012
Award Type: Pilot
Award Amount: $104,762
Experimentally, curcumin (turmeric spice) has been implicated in resolving and preventing Alzheimer's disease associated plaques or deposits both in living systems and in test tubes. Epidemiological data suggest that the consumption of curcumin is linked to a lower incidence of Alzheimer's disease. However, the solubility of curcumin in watery solutions is exceedingly low, which limits its systemic absorption and therapeutic potential. A new method is proposed to treat or prevent amyloid plaque formation associated with Alzheimer's disease by injection of highly concentrated blood serum-solubilized curcumin.
Our previous research has largely been focused on investigating the regulation of genes associated with Alzheimer's disease. However, upon learning about the epidemiological link between a lower incidence of Alzheimer disease and the consumption of the spice turmeric, I became interested in the compound curcumin, which is an active ingredient in turmeric. Upon attempting to expose cultured cells to curcumin, I became aware of the technical problems in solubilizing the compound and measuring its concentration. In over 2,000 publications about this compound, the issue of solubility was never or rarely addressed. Hence, I proceeded to develop a novel method to solubilize curcumin in blood serum and to reliably measure its concentration. The concentration of curcumin achieved in serum is at least 1,000-fold higher than the concentration necessary to resolve or prevent deposits associated with Alzheimer's disease. Therefore, the serum-solubilized curcumin lends itself to therapeutic application by intravenous injection of small amounts of serum derived from the patient's own blood. Using the patient's own serum prevents the transmission of blood-borne diseases and potential immunological reactions. The feasibility of such a treatment option will be investigated in this proposal. For this purpose transgenic mice will be used that have been designed to develop Alzheimer's disease associated plaques. The proposal will specifically address the following questions:
1. How does the injection of curcumin-enriched serum affect its bioavailability?
2. Can such injected serum prevent plaque formation in mice?
3. Can injected serum-solubilized curcumin resolve preexisting plaques in transgenic mice?
Quitschke, W. W. (2012) Curcuminoid binding to embryonal carcinoma cells: reductive metabolism, induction of apoptosis, senescence, and inhibition of cell proliferation. PLoS One, 7, e39568.
Quitschke WW, Steinhauff N, Rooney J. The effect of cyclodextrin-solubilized curcuminoids on amyloid plaques in Alzheimer transgenic mice: brain uptake and metabolism after intravenous and subcutaneous injection. Alzheimers Res Ther. 2013 Mar 28;5(2):16.
In an initial round of experiments carried out by Dr. Quitschke’s team of researchers, curcumin was solubilized in blood serum derived from and tested on rats of the same strain without adverse effect. Particular concerns were that curcumin might have toxic effects or that the injected serum might induce allergic reactions. However, using the same protocol on mice engineered to have Alzheimer’s disease did produce adverse reactions after multiple injections. This necessitated the use of an alternative delivery vehicle for getting curcumin into solution (i.e. cyclodextrin).
For the analysis of plaque prevention, the Alzheimer’s mice were intravenously injected with the new curcumin cyclodextrin solutions once per week for 6 months. For the remaining 6-8 weeks, injections needed to be continued subcutaneously due to extensive deterioration of the tail vein at the site of injections. Preliminary analysis showed a 10-15% reduction of plaque load in treated animals relative to controls. The ability of intravenously injected curcumin solutions to resolve existing plaques was assessed by injecting Alzheimer’s mice twice per week between the ages of 11-12 months. For this set of experiments, the team used a curcumin dose 4-fold higher than in the plaque prevention experiments. This resulted in a plaque reduction of about 30% relative to controls. Although these results are encouraging, they did not provide an extensive reduction of plaques. Therefore, the team further investigated the bioavailability of injected curcumin.
They found that intravenously injected curcumin was rapidly cleared from circulation and tissues by metabolic conversion. After 60 minutes, essentially all of the curcumin and metabolites were eliminated from the system. Surprisingly, the curcumin levels achieved in the brain were unexpectedly high and maximum concentrations were delayed until several minutes after injection. In contrast to serum and other organs, the brain didn’t contain certain inactive curcumin metabolites (called conjugated metabolites). Instead, relatively high levels of curcumin remained for up to 30 minutes while being locally metabolized (converted by reduction). This raises the possibility that curcumin levels in the brain could be high enough to enable binding to amyloid plaques, and that plaque prevention and resolution could be further enhanced by increasing the exposure to curcumin.