Curcumin micelles improve mitochondrial function in neuronal PC12 cells and brains of NMRI mice – Impact on bioavailability
Introduction
Curcumin is the most abundant polyphenolic compound of the Indian spice turmeric (Curcuma longa) and has long been used as spice and remedy in Asian countries (Esatbeyoglu et al., 2012). Curcumin has a lot of health-promoting effects, amongst them antioxidant, antibacterial, anti-inflammatory, analgesic, anti-protein-aggregation, wound-healing and eupeptic properties (Cole et al., 2007, Esatbeyoglu et al., 2012, Ringman et al., 2005, Villaflores et al., 2012). Several preclinical and clinical studies suggest that curcumin has preventive and therapeutic effects in cancer, atherosclerosis, aging, neurodegenerative diseases, obesity and diabetes (Aggarwal and Harikumar, 2009, Aggarwal et al., 2003, Ringman et al., 2005). We recently reported that curcumin administration ameliorated brain mitochondrial dysfunction in senescence-accelerated mice (Eckert et al., 2013) as well as in a mouse model of Alzheimer's disease (Hagl et al., 2014).
Mitochondrial dysfunction has been found to occur at an early stage in brain aging as well as in various neurodegenerative diseases like Alzheimer's disease, Parkinson's disease and Huntington's disease (Boveris and Navarro, 2008, Leuner et al., 2007, Moura et al., 2010, Müller et al., 2010). Mitochondrial dysfunction in aging and neurodegenerative diseases comprises decreased mitochondrial membrane potential and ATP levels, decreased respiratory capacity as well as increased levels of oxidative stress, mitochondrial permeability transition pore (mPTP) opening and programmed cell death (Boveris and Navarro, 2008, Chistiakov et al., 2014, Leuner et al., 2007, Müller et al., 2010, Navarro and Boveris, 2010). Components that are able to ameliorate mitochondrial dysfunction are considered as suitable substances for the prevention of brain aging and neurodegenerative diseases. Due to the above mentioned health-promoting effects, curcumin might be a promising component for this application (Asseburg et al., 2014).
Curcumin bioavailability is generally rather low as it is hardly absorbed in the small intestine and quickly eliminated via the gall bladder after being metabolized in the liver (Anand et al., 2007, Esatbeyoglu et al., 2012). Oral administration of high curcumin doses (up to 12 g) to humans, for example, led to peak plasma concentrations in the nanomolar range 1 h after administration (Esatbeyoglu et al., 2012). Therefore the major problem for the use of curcumin as therapeutic agent is its low bioavailability following oral administration.
There are several approaches to ameliorate curcumin bioavailability after oral administration. For example, curcumin can be administered simultaneously with secondary plant compounds like piperine, ferulic acid or resveratrol to retard curcumin metabolism (Anand et al., 2007). Furthermore, curcumin can be incorporated into liposomes, phospholipids or nanoparticles to increase absorption in the intestine. Xie and co-workers showed that polylactic-co-glycolic acid-coated (PLGA-coated) nanoparticles of curcumin increased oral curcumin bioavailability in rats by five-to six fold (Xie et al., 2011). Incorporation of curcumin into lecithin liposomes has also been reported to increase oral bioavailability in rats by 5-fold (Takahashi et al., 2009). We recently showed that both micronized curcumin powder (9-fold increase) and in particular a liquid micellar formulation of curcumin (185-fold increase) significantly improved oral bioavailability of curcumin without altering safety parameters in healthy humans (Schiborr et al., 2014).
In this work we examined bioavailability and biological effects of this newly developed curcumin formulation, namely curcumin micelles, in NMRI mice and PC12 cells. Curcumin micelles are supposed to mimic physiological micelles that are formed in the intestine to allow absorption of lipophilic food ingredients. We hypothesize that due to increased bioavailability of curcumin micelles, curcumin concentrations in the brain will be elevated which might increase neuroprotective effects of curcumin.
Section snippets
Chemicals
Unless otherwise stated, chemicals were of highest available purity and purchased from Sigma (St. Louis, MO, USA) or Merck (Darmstadt, Germany). Aqueous solutions were prepared with deionized, filtered water (Millipore, Billerica, MA, USA). The native curcumin powder was obtained from Jupiter Leys (Cochin, Kerala State, India) and contained 82% curcumin, 16% demethoxycurcumin (DMC), and 2% bisdemethoxycurcumin (BDMC). Curcumin micelles and reference micelles were manufactured by Aquanova AG
Results
In a first experiment we examined the bioavailability of native curcumin and curcumin micelles in murine blood plasma and brain tissue. Additionally, mitochondrial function was assessed in mouse brain after a three-week administration (120 μg curcumin/g body weight/day) of curcumin micelles. To shed light on the mechanism of action of curcumin, mitochondrial swelling as a consequence of mitochondrial permeability transition pore (mPTP) opening was examined in isolated mouse brain mitochondria
Discussion
We examined bioavailability as well as the effects of native curcumin and the new formulation curcumin micelles on mitochondrial function in in vitro and in vivo models to determine if curcumin micelles could improve both bioavailability and mitochondria-protective effects of curcumin.
Conclusion
We found that curcumin micelles, a newly developed curcumin preparation, improved bioavailability of curcumin around 10- to 40-fold in murine plasma and brain tissue. Furthermore curcumin micelles proved to be more efficient in protecting PC12 cells from nitrosative stress and preventing isolated mitochondria from swelling. Therefore curcumin micelles might be a suitable substance for the prevention of mitochondrial dysfunction and neurodegeneration which both may promote age-associated
Conflicts of interest
Curcumin micelles were provided by Aquanova in the frame of a joint research project supported by the German Federal Ministry of Education and Research. The authors declare no conflict of interest.
Acknowledgments
This work was supported by the German Federal Ministry of Education and Research (grant no. 01EA1334A and 01EA1334B).
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