Curcumin (CUR), a natural polyphenolic compound, is considered as one of the most potential candidates against Alzheimer disease (AD) by targeting multiple pathologies such as amyloid-beta, tau phosphorylation, and oxidative stress. Poor physicochemical profile and oral bioavailability (BA) are the major contributors to its failure in clinical trials. Lack of success in numerous drug clinical trials for the treatment of AD urges the need of repositioning of CUR. To overcome its limitation and enhance oral BA, Novel CUR Formulation (NCF) was developed using self-nanomicellizing solid dispersion strategy which displayed 117-fold enhancement in oral BA of CUR. NCF was tested using SH-SY5Y695 APP human neuroblastoma cell line against the cytotoxicity induced by copper metal ion, H2O2, and Aβ42 oligomer and compared with CUR control. The safety and efficacy of NCF on mice AD-like behavioral deficits (open field, novel objective recognition, Y-maze, and Morris water maze tests) were assessed in transgenic AD (APPSwe/PS1deE9) mice model. In SH-SY5Y695 APP human neuroblastoma cell line, NCF showed better safety and efficacy against the cytotoxicity due to the significantly enhancement of cellular uptake. It not only prevents the deterioration of cognitive functions of the aged APPSwe/PS1deE9 mice during aging but also reverses the cognitive functions to their much younger age which is also better than the currently available approved options. Moreover, NCF was proved as well tolerated with no appearance of any significant toxicity via oral administration. The results of the study demonstrated the potential of NCF to improve the efficacy of CUR without compromising its safety profile, and pave the way for clinical development for AD.
This is a preview of subscription content, access via your institution.
Buy single article
Instant access to the full article PDF.
Tax calculation will be finalised during checkout.
Subscribe to journal
Immediate online access to all issues from 2019. Subscription will auto renew annually.
Tax calculation will be finalised during checkout.
Roberson ED, Mucke L. 100 years and counting: prospects for defeating Alzheimer’s disease. Science. 2006;314(5800):781–4. https://doi.org/10.1126/science.1132813.
Mangialasche F, Solomon A, Winblad B, Mecocci P, Kivipelto M. Alzheimer’s disease: clinical trials and drug development. The Lancet Neurology. 2010;9(7):702–16. https://doi.org/10.1016/S1474-4422(10)70119-8.
Iqbal K, Liu F, Gong CX. Alzheimer disease therapeutics: focus on the disease and not just plaques and tangles. Biochem Pharmacol. 2014;88:631–9. https://doi.org/10.1016/j.bcp.2014.01.002.
Schneider LS, Mangialasche F, Andreasen N, Feldman H, Giacobini E, Jones R, et al. Clinical trials and late-stage drug development for Alzheimer’s disease: an appraisal from 1984 to 2014. J Intern Med. 2014;275(3):251–83. https://doi.org/10.1111/joim.12191.
Mishra S, Palanivelu K. The effect of curcumin (turmeric) on Alzheimer’s disease: an overview. Annals of Indian Academy of Neurology. 2008;11(1):13–9. https://doi.org/10.4103/0972-2327.40220.
Zeng YQ, Wang YJ, Zhou XF. Effects of (−)epicatechin on the pathology of APP/PS1 transgenic mice. Front Neurol. 2014;5:69. https://doi.org/10.3389/fneur.2014.00069.
Wang YJ, Thomas P, Zhong JH, Bi FF, Kosaraju S, Pollard A, et al. Consumption of grape seed extract prevents amyloid-beta deposition and attenuates inflammation in brain of an Alzheimer’s disease mouse. Neurotox Res. 2009;15(1):3–14. https://doi.org/10.1007/s12640-009-9000-x.
Ringman JM, Frautschy SA, Teng E, Begum AN, Bardens J, Beigi M, et al. Oral curcumin for Alzheimer’s disease: tolerability and efficacy in a 24-week randomized, double blind, placebo-controlled study. Alzheimers Res Ther. 2012;4(5):43. https://doi.org/10.1186/alzrt146.
Mecocci P, Polidori MC. Antioxidant clinical trials in mild cognitive impairment and Alzheimer’s disease. Biochim Biophys Acta. 2012;1822(5):631–8. https://doi.org/10.1016/j.bbadis.2011.10.006.
Anand P, Kunnumakkara AB, Newman RA, Aggarwal BB. Bioavailability of curcumin: problems and promises. Mol Pharm. 2007;4(6):807–18. https://doi.org/10.1021/mp700113r.
Parikh A, Kathawala K, Tan CC, Garg S, Zhou XF. Development of a novel oral delivery system of edaravone for enhancing bioavailability. Int J Pharm. 2016;515(1–2):490–500. https://doi.org/10.1016/j.ijpharm.2016.10.052.
Parikh A, Kathawala K, Tan CC, Garg S, Zhou XF. Lipid-based nanosystem of edaravone: development, optimization, characterization and in vitro/in vivo evaluation. Drug delivery. 2017;24(1):962–78. https://doi.org/10.1080/10717544.2017.1337825.
Parikh A, Kathawala K, Tan CC, Garg S, Zhou X-F. Self-nanomicellizing solid dispersion of edaravone: part I; oral bioavailability improvement. Drug design, development and therapy. 2018;12:2051–69. https://doi.org/10.2147/dddt.s161940.
Parikh A, Kathawala K, Song Y, Zhou XF, Garg S. Curcumin-loaded self-nanomicellizing solid dispersion system: part I: development, optimization, characterization, and oral bioavailability. Drug delivery and translational research. 2018; https://doi.org/10.1007/s13346-018-0543-3.
Parikh A, Kathawala K, Li J, Chen C, Shan Z, Cao X, et al. Self-nanomicellizing solid dispersion of edaravone: part II: in vivo assessment of efficacy against behavior deficits and safety in Alzheimer’s disease model. Drug design, development and therapy. 2018;12:2111–28. https://doi.org/10.2147/dddt.s161944.
Teixeira CC, Mendonca LM, Bergamaschi MM, Queiroz RH, Souza GE, Antunes LM, et al. Microparticles containing curcumin solid dispersion: stability. Bioavailability and anti-inflammatory activity AAPS pharmSciTech. 2016;17(2):252–61. https://doi.org/10.1208/s12249-015-0337-6.
Wang C, Ma C, Wu Z, Liang H, Yan P, Song J, et al. Enhanced bioavailability and anticancer effect of curcumin-loaded electrospun nanofiber: in vitro and in vivo study. Nanoscale Res Lett. 2015;10(1):439. https://doi.org/10.1186/s11671-015-1146-2.
Patil S, Choudhary B, Rathore A, Roy K, Mahadik K. Enhanced oral bioavailability and anticancer activity of novel curcumin loaded mixed micelles in human lung cancer cells. Phytomedicine : international journal of phytotherapy and phytopharmacology. 2015;22(12):1103–11. https://doi.org/10.1016/j.phymed.2015.08.006.
Hagl S, Heinrich M, Kocher A, Schiborr C, Frank J, Eckert GP. Curcumin micelles improve mitochondrial function in a mouse model of Alzheimer’s disease. The Journal of Prevention of Alzheimer’s Disease. 2014;1(2):80–3.
Buckholtz NS, Ryan LM, Petanceska S, Refolo LM. NIA commentary: translational issues in Alzheimer’s disease drug development. Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology. 2012;37(1):284–6. https://doi.org/10.1038/npp.2011.116.
LaFerla FM, Green KN. Animal models of Alzheimer disease. Cold Spring Harbor perspectives in medicine. 2012; 2(11). https://doi.org/10.1101/cshperspect.a006320.
Saraceno C, Musardo S, Marcello E, Pelucchi S, Di Luca M. Modeling Alzheimer’s disease: from past to future. Front Pharmacol. 2013;4:77. https://doi.org/10.3389/fphar.2013.00077.
Russo P, Kisialiou A, Lamonaca P, Moroni R, Prinzi G, Fini M. New drugs from marine organisms in Alzheimer’s disease. Marine drugs. 2015;14(1):5. https://doi.org/10.3390/md14010005.
Wang YJ, Pollard A, Zhong JH, Dong XY, Wu XB, Zhou HD, et al. Intramuscular delivery of a single chain antibody gene reduces brain Abeta burden in a mouse model of Alzheimer’s disease. Neurobiol Aging. 2009;30(3):364–76. https://doi.org/10.1016/j.neurobiolaging.2007.06.013.
Yao XQ, Jiao SS, Saadipour K, Zeng F, Wang QH, Zhu C, et al. p75NTR ectodomain is a physiological neuroprotective molecule against amyloid-beta toxicity in the brain of Alzheimer’s disease. Mol Psychiatry. 2015;20(11):1301–10. https://doi.org/10.1038/mp.2015.49.
Jiao SS, Yao XQ, Liu YH, Wang QH, Zeng F, Lu JJ, et al. Edaravone alleviates Alzheimer’s disease-type pathologies and cognitive deficits. Proc Natl Acad Sci U S A. 2015;112(16):5225–30. https://doi.org/10.1073/pnas.1422998112.
Christakis DA, Ramirez JS, Ramirez JM. Overstimulation of newborn mice leads to behavioral differences and deficits in cognitive performance. Sci Rep. 2012;2:546. https://doi.org/10.1038/srep00546.
Ruan CS, Yang CR, Li JY, Luo HY, Bobrovskaya L, Zhou XF. Mice with Sort1 deficiency display normal cognition but elevated anxiety-like behavior. Exp Neurol. 2016;281:99–108. https://doi.org/10.1016/j.expneurol.2016.04.015.
Zhang Q, Gao X, Li C, Feliciano C, Wang D, Zhou D, et al. Impaired dendritic development and memory in Sorbs2 knock-out mice. J Neurosci. 2016;36(7):2247–60. https://doi.org/10.1523/jneurosci.2528-15.2016.
Bakoma B, Berke B, Eklu-Gadegbeku K, Agbonon A, Aklikokou K, Gbeassor M, et al. Acute and sub-chronic (28days) oral toxicity evaluation of hydroethanolic extract of Bridelia ferruginea Benth root bark in male rodent animals. Food Chem Toxicol. 2013;52:176–9. https://doi.org/10.1016/j.fct.2012.11.021.
Zhang Q, Li J, Zhang W, An Q, Wen J, Wang A, et al. Acute and sub-chronic toxicity studies of honokiol microemulsion. Regul Toxicol Pharmacol. 2014;71(3):428–36. https://doi.org/10.1016/j.yrtph.2014.11.007.
Wang L, Li Z, Li L, Li Y, Yu M, Zhou Y, et al. Acute and sub-chronic oral toxicity profiles of the aqueous extract of Cortex Dictamni in mice and rats. J Ethnopharmacol. 2014;158(Pt A):207–15. https://doi.org/10.1016/j.jep.2014.10.027.
Arjo G, Capell T, Matias-Guiu X, Zhu C, Christou P, Pinol C. Mice fed on a diet enriched with genetically engineered multivitamin corn show no sub-acute toxic effects and no sub-chronic toxicity. Plant Biotechnol J. 2012;10(9):1026–34. https://doi.org/10.1111/j.1467-7652.2012.00730.x.
West MJ. Regionally specific loss of neurons in the aging human hippocampus. Neurobiol Aging. 1993;14(4):287–93.
Arendash GW, King DL, Gordon MN, Morgan D, Hatcher JM, Hope CE, et al. Progressive, age-related behavioral impairments in transgenic mice carrying both mutant amyloid precursor protein and presenilin-1 transgenes. Brain Res. 2001;891:42–53.
Francis PT, Nordberg A, Arnold SE. A preclinical view of cholinesterase inhibitors in neuroprotection: do they provide more than symptomatic benefits in Alzheimer’s disease? Trends Pharmacol Sci. 2005;26(2):104–11. https://doi.org/10.1016/j.tips.2004.12.010.
Antunes M, Biala G. The novel object recognition memory: neurobiology, test procedure, and its modifications. Cogn Process. 2012;13(2):93–110. https://doi.org/10.1007/s10339-011-0430-z.
Hebert-Chatelain E, Desprez T, Serrat R, Bellocchio L, Soria-Gomez E, Busquets-Garcia A, et al. A cannabinoid link between mitochondria and memory. Nature. 2016;539(7630):555–9. https://doi.org/10.1038/nature20127.
Wolf A, Bauer B, Abner EL, Ashkenazy-Frolinger T, Hartz AM. A comprehensive behavioral test battery to assess learning and memory in 129S6/Tg2576 mice. PLoS One. 2016;11(1):e0147733. https://doi.org/10.1371/journal.pone.0147733.
Vorhees CV, Williams MT. Morris water maze: procedures for assessing spatial and related forms of learning and memory. Nat Protoc. 2006;1(2):848–58. https://doi.org/10.1038/nprot.2006.116.
Wang P, Su C, Li R, Wang H, Ren Y, Sun H, et al. Mechanisms and effects of curcumin on spatial learning and memory improvement in APPswe/PS1dE9 mice. J Neurosci Res. 2014;92(2):218–31. https://doi.org/10.1002/jnr.23322.
Tiwari SK, Agarwal S, Seth B, Yadav A, Nair S, Bhatnagar P, et al. Curcumin-loaded nanoparticles potently induce adult neurogenesis and reverse cognitive deficits in Alzheimer’s disease model via canonical Wnt/beta-catenin pathway. ACS Nano. 2014;8(1):76–103. https://doi.org/10.1021/nn405077y.
Kim DC, Ku SK, Bae JS. Anticoagulant activities of curcumin and its derivative. BMB Rep. 2012;45(4):221–6.
Takashi Ikeo IS. Age-related changes in hematology and serum biochemistry values in SAMR1 and SAMP8 mice. Shikaigaku. 2001;64(4):358–68. https://doi.org/10.18905/shikaigaku.64.4_358.
Prof. Xin-Fu Zhou is grateful for the NHMRC fellowship. Ankit Parikh is obliged for the University President’s Scholarships from University of South Australia. Dr. Jintao Li is a visiting scholar and grateful for a scholarship under state scholarship fund organized by China Scholarship Council (CSC). We thank H. Md. Morshed Alam (BASF Australia Ltd.) for generously providing SOL, Rupal Pradhan and Andrew Beck from University of South Australia for technical support in hematological, coagulation parameters and histology study, Rebecca Summerton and Dr. Ian Beckman from Veterinary Diagnostic Laboratory, the University of Adelaide for providing technical support for serum biochemistry study, and Noralyn Manucat-Tan and Chun-Sheng Ruan for behavior tests. The Reid animal house staff members from University of South Australia are acknowledged for generous support in animal work.
This study received financial support from Fujian Kangshimei Co., China for the present research.
All breeding procedures were approved by the Animal Ethics Committee of the University of South Australia.
Conflict of interest
Ankit Parikh, Xin-Fu Zhou, and Sanjay Garg are the named inventors of Chinese patent 201610267974.5. Fujian Kangshimei Co., China owns the intellectual property. There is no other potential conflict of interest relevant to this article.
Electronic supplementary material
About this article
Cite this article
Parikh, A., Kathawala, K., Li, J. et al. Curcumin-loaded self-nanomicellizing solid dispersion system: part II: in vivo safety and efficacy assessment against behavior deficit in Alzheimer disease. Drug Deliv. and Transl. Res. 8, 1406–1420 (2018). https://doi.org/10.1007/s13346-018-0570-0
- APPSwe/PS1deE9 mice
- Learning and memory
- Safety assessment