The effect of cyclodextrin-solubilized curcuminoids on amyloid plaques in Alzheimer transgenic mice: brain uptake and metabolism after intravenous and subcutaneous injection

Abstract

IntroductionCurcuminoids may improve pathological conditions associated with Alzheimer's disease. However, their therapeutic potential is limited by their exceedingly low bioavailability after oral administration. A method to deliver solubilized curcuminoids by injection was evaluated in Alzheimer transgenic mice.MethodsAmyloid protein precursor (APP)SWE, PS1dE9 mice were intravenously or subcutaneously injected at weekly intervals between the ages of 4 and 12 months with serum- or cyclodextrin-solubilized curcuminoids to assess their potential for plaque prevention. Alternatively, mice between the ages of 11 and 12 months were intravenously injected with cyclodextrin-solubilized curcuminoids at biweekly intervals to evaluate their ability to eliminate existing plaques. Plasma and brain levels of curcuminoids and their metabolites were also determined after subcutaneous and intravenous injection.ResultsWeekly long-term injections did not result in a significant plaque load reduction. However, intravenous injection of cyclodextrin-solubilized curcuminoids at higher curcuminoid concentrations and at a biweekly frequency between the ages of 11 and 12 months reduced the plaque load to approximately 70% of the control value. After intravenous injection, plasma levels of 100 μM curcuminoids and brain levels of 47 nmol/g could initially be achieved that declined to essentially undetectable levels within 20 minutes. The primary curcuminoid metabolites in plasma were the conjugates of glucuronide or sulfate and hexahydrocurcuminoids as reduction products. In the brain, both hexahydrocurcuminoids and octahydrocurcuminoids were detected as major metabolites. After subcutaneous injection, maximal curcuminoid plasma levels of 23 μM and brain levels of 8 nmol/g were observed at 30 minutes after injection and curcuminoids remained detectable for 2 to 3 h.ConclusionCurcuminoids are rapidly metabolized after injection and their effect on reducing plaque load associated with Alzheimer's disease may be dependent on the frequency of administration.