Skip to main content

Advertisement

Log in

Brain Targeted Curcumin Loaded Turmeric Oil Microemulsion Protects Against Trimethyltin Induced Neurodegeneration in Adult Zebrafish: A Pharmacokinetic and Pharmacodynamic Insight

  • Original Research Article
  • Published:
Pharmaceutical Research Aims and scope Submit manuscript

Abstract

Purpose

Aromatic turmerone, a major constituent of turmeric oil, has been recently reported for proliferation of neural stem cell showing great potential for effective treatment in neurodegenerative disorders. However, its effect as oral brain targeted formulation for neuroprotection has not yet reported. The objective of the study was to investigate the pharmacokinetic of curcumin loaded turmeric oil microemulsion for brain targeting and probing the protective effect against trimethyltin induced neurodegeneration in adult zebrafish.

Methods

Initially, in vivo plasma and brain pharmacokinetics was performed to determine improvement in relative bioavailability in rats followed by biodistribution and histopathological evaluation. Furthermore, the neuroprotective effect of the formulation was assessed in trimethyltin induced neurodegeneration model using adult zebrafish by behavioral analysis and biochemical analysis.

Results

The in vivo plasma and brain pharmacokinetics showed 2-fold and 1.87-fold improvement respectively. Biodistribution study revealed significantly lower concentration in organs other than brain. Furthermore, curcumin microemulsion exhibited improved spatial memory by remembering the training and made correct choices after curcumin microemulsion treatment than other treatment groups. Histopathological evaluation confirmed neuroprotective effect on zebrafish brains. The biochemical analysis revealed reduced oxidative stress in curcumin microemulsion treated group.

Conclusions

Overall results showed a great potential of curcumin microemulsion for brain targeting in the effective treatment of neurological ailments.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7

Similar content being viewed by others

Data Availability

Data available on request.

References

  1. Feigin VL, Nichols E, Alam T, Bannick MS, Beghi E, Blake N, et al. Global, regional, and national burden of neurological disorders, 1990–2016: a systematic analysis for the Global Burden of Disease Study 2016. Lancet Neurol. 2019;18:459–80.

    Article  Google Scholar 

  2. Darvesh AS, Carroll RT, Bishayee A, Novotny NA, Geldenhuys WJ, Van der Schyf CJ. Curcumin and neurodegenerative diseases: a perspective. Expert Opin Investig Drugs [Internet]. 2012;21:1123–40. Available from: http://www.tandfonline.com/doi/full/10.1517/13543784.2012.693479

  3. Raghavan A, Shah ZA. Neurodegenerative disease. Diet, Exerc Chronic Dis Biol Basis Prev. 2014;339–90.

  4. Dos S-N, De Vilhena Toledo MA, Medeiros-Souza P, De Souza GA. The use of herbal medicine in Alzheimer’s disease - A systematic review. Evidence-based Complement Altern Med. 2006;3:441–5.

    Article  Google Scholar 

  5. Bharat B. A, Chitra S, Nikita M, Haruyo I. Curcumin: The Indian solid gold. Adv Exp Med Biol [Internet]. 2007;595:1–75. Available from: http://www.embase.com/search/results?subaction=viewrecord&from=export&id=L354122020

  6. Maheshwari RK, Singh AK, Gaddipati J, Srimal RC. Multiple biological activities of curcumin: A short review. Life Sci [Internet]. Elsevier B.V.; 2006;78:2081–7. Available from: https://doi.org/10.1016/j.lfs.2005.12.007

  7. Mythri RB, Srinivas Bharath MM. Curcumin: a potential neuroprotective agent in parkinson’s disease. Curr Pharm Des. 2012;18:91–9.

    Article  CAS  PubMed  Google Scholar 

  8. Perrone D, Ardito F, Giannatempo G, Dioguardi M, Troiano G, Lo Russo L, et al. Biological and therapeutic activities, and anticancer properties of curcumin (Review). Exp Ther Med. 2015;10:1615–23.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Shehzad A, Islam SU, Lee YS. Curcumin and Inflammatory Brain Diseases. Curcumin Neurol Psychiatr Disord. 2019. p. 437–58.

  10. Hamaguchi T, Ono K, Yamada M. Curcumin and Alzheimer’s disease. CNS Neurosci Ther. 2010;16:285–97.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Liu W, Zhai Y, Heng X, Che FY, Chen W, Sun D, et al. Oral bioavailability of curcumin: problems and advancements. J Drug Target [Internet]. 2016;2330:1–9. Available from: http://www.scopus.com/inward/record.url?eid=2-s2.0-84961217782&partnerID=tZOtx3y1

  12. Prasad S, Tyagi AK, Aggarwal BB. Recent developments in delivery, bioavailability, absorption and metabolism of curcumin: The golden pigment from golden spice. Cancer Res Treat. 2014;46:2–18.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Hucklenbroich J, Klein R, Neumaier B, Graf R, Fink G, Schroeter M, et al. Aromatic-turmerone induces neural stem cell proliferation in vitro and in vivo. Stem Cell Res Ther [Internet]. 2014;5:100. Available from: http://stemcellres.com/content/5/4/100

  14. Lee Y. Activation of apoptotic protein in U937 cells by a component of turmeric oil. BMB Rep [Internet]. 2009;42:96–100. Available from: http://koreascience.or.kr/journal/view.jsp?kj=E1MBB7&py=2009&vnc=v42n2&sp=96

  15. Lee J. Induction of apoptosis by ar-turmerone on various cell lines. Int J Mol Med [Internet]. 2004;14:253–6. Available from: https://www.spandidos-publications.com/10.3892/ijmm.14.2.253

  16. Jankasem M, Wuthi-udomlert M, Gritsanapan W. Antidermatophytic Properties of Ar -Turmerone , Turmeric Oil , and Curcuma longa Preparations. 2013;2013.

  17. Park SY, Jin ML, Kim YH, Kim Y, Lee SJ. Anti-inflammatory effects of aromatic-turmerone through blocking of NF-κB, JNK, and p38 MAPK signaling pathways in amyloid β-stimulated microglia. Int Immunopharmacol [Internet]. Elsevier B.V.; 2012;14:13–20. Available from: https://doi.org/10.1016/j.intimp.2012.06.003

  18. Park SY, Kim YH, Lee S-J. Aromatic-turmerone’s anti-inflammatory effects in microglial cells are mediated by protein kinase A and heme oxygenase-1 signaling. Neurochem Int [Internet]. Elsevier Ltd; 2012;61:767–77. Available from: http://www.ncbi.nlm.nih.gov/pubmed/22766494

  19. Park SY, Kim YH, Kim Y, Lee SJ. Aromatic-turmerone attenuates invasion and expression of MMP-9 and COX-2 through inhibition of NF-??B activation in TPA-induced breast cancer cells. J Cell Biochem. 2012;113:3653–62.

    Article  CAS  PubMed  Google Scholar 

  20. Yue GGL, Cheng S-W, Yu H, Xu Z, Lee JKM, Hon P-M, et al. The role of turmerones on curcumin transportation and p-glycoprotein activities in intestinal caco-2 cells. J Med Food [Internet]. 2012;15:242–52. Available from: http://www.liebertpub.com/doi/10.1089/jmf.2011.1845

  21. Benny A, Moni Abraham K, Mani Georgekutty P. Formulation of curcumin with enhanced bioavailability of curcumin and method of preparation and treatment thereof [Internet]. United States; 2019. Available from: https://patents.google.com/patent/US20200108148A1/en

  22. More SK, Pawar AP. Preparation, optimization and preliminary pharmacokinetic study of curcumin encapsulated turmeric oil microemulsion in zebra fish. Eur J Pharm Sci [Internet]. Elsevier; 2020;155:105539. Available from: https://doi.org/10.1016/j.ejps.2020.105539

  23. Zhang C, Willett C, Fremgen T. Zebrafish: an animal model for toxicological studies. Curr Protoc Toxicol [Internet]. 2003;1.7.1–1.7.18. Available from: http://onlinelibrary.wiley.com/doi/10.1002/0471140856.tx0107s17/full

  24. Dooley K, Zon LI. Zebrafish: a model system for the study of human disease. Curr Opin Genet Dev. 2000;10:252–6.

    Article  CAS  PubMed  Google Scholar 

  25. Pickart MA, Klee EW. Zebrafish approaches enhance the translational research tackle box. Transl Res [Internet]. Mosby, Inc; 2014;163:65–78. Available from: https://doi.org/10.1016/j.trsl.2013.10.007

  26. Chakraborty C, Hsu CH, Wen ZH, Lin CS, Agoramoorthy G. Zebrafish: a complete animal model for in vivo drug discovery and development. Curr Drug Metab [Internet]. 2009;10:116–24. Available from: http://www.ncbi.nlm.nih.gov/pubmed/19275547

  27. Newman M, Verdile G, Martins RN, Lardelli M. Zebrafish as a tool in Alzheimer’s disease research. Biochim Biophys Acta - Mol Basis Dis. 2011;1812:346–52.

    Article  CAS  Google Scholar 

  28. Newman M, Ebrahimie E, Lardelli M. Using the zebrafish model for Alzheimer’s disease research. Front Genet. 2014;5:1–10.

    Article  Google Scholar 

  29. Surendra V, Raj Sharma U, Goli D. Behavioral studies of different drugs using zebrafish as a model. Int J Pharmagenes [Internet]. 2011;2:75–82. Available from: http://serialsjournals.com/serialjournalmanager/pdf/1331634585.pdf

  30. Kumar B, Tharumasivam SV, Boominathan V, Perumal E, Dhandapani P, Kaliyaperumal K, et al. A pilot study on nanotherapy of momordica charantia against trimethyltin chloride-induced neurotoxicity in danio rerio (Zebrafish). J Nanomater. 2021;2021.

  31. Williams FE, White D, Messer WS. A simple spatial alternation task for assessing memory function in zebrafish. Behav Processes. 2002;58:125–32.

    Article  PubMed  Google Scholar 

  32. Koehler D, Shah ZA, Hensley K, Williams FE. Lanthionine ketimine-5-ethyl ester provides neuroprotection in a zebrafish model of okadaic acid-induced Alzheimer’s disease. Neurochem Int [Internet]. Elsevier Ltd; 2018;115:61–8. Available from: https://doi.org/10.1016/j.neuint.2018.02.002

  33. Avdesh A, Chen M, Martin-iverson MT, Verdile G, Mondal A, Martins RN. Natural colour preference in the zebrafish (Danio rerio). Proc Meas Behav [Internet]. 2010;2010:155–7. Available from: http://measuringbehavior.org/files/ProceedingsPDF(website)/Avdesh_FullPaper1.7.pdf

  34. Dawn S, Mohammad KA. An assessment of zebrafish natural color preference and its modification by stimuli. J Mood Disord Ther. 2017;1:17–23.

    Article  Google Scholar 

  35. Anand SK, Sahu MR, Mondal AC. Induction of oxidative stress and apoptosis in the injured brain: potential relevance to brain regeneration in zebrafish. Mol Biol Rep [Internet]. Springer Netherlands; 2021;48:5099–108. Available from: https://doi.org/10.1007/s11033-021-06506-7

  36. Buege JA, Aust SD. Biomembranes - part C: Biological oxidations. Methods Enzymol [Internet]. 1978;52:302–10. Available from: http://www.sciencedirect.com/science/article/pii/S0076687978520326

  37. Beauchamp C, Fridovich I. Superoxide dismutase: Improved assays and an assay applicable to acrylamide gels. Anal Biochem. 1971;44:276–87.

    Article  CAS  PubMed  Google Scholar 

  38. Kharat S, Namdeo A, Mehta P. Development and validation of HPTLC method for simultaneous estimation of curcumin and galangin in polyherbal capsule dosage form. J Taibah Univ Sci [Internet]. Taibah University; 2017;11:775–81. Available from: https://doi.org/10.1016/j.jtusci.2016.10.004

  39. Ipar VS, Dsouza A, Devarajan P V. Enhancing curcumin oral bioavailability through nanoformulations. Eur J Drug Metab Pharmacokinet [Internet]. Springer International Publishing; 2019; Available from: https://doi.org/10.1007/s13318-019-00545-z

  40. Lazar AN, Mourtas S, Youssef I, Parizot C, Dauphin A, Delatour B, et al. Curcumin-conjugated nanoliposomes with high affinity for A β deposits : Possible applications to Alzheimer disease. Nanomedicine Nanotechnology, Biol Med [Internet]. Elsevier Inc.; 2013;9:712–21. Available from: https://doi.org/10.1016/j.nano.2012.11.004

  41. Mourtas S, Lazar AN, Markoutsa E, Duyckaerts C, Antimisiaris SG. Multifunctional nanoliposomes with curcumin-lipid derivative and brain targeting functionality with potential applications for Alzheimer disease. Eur J Med Chem [Internet]. Elsevier Masson SAS; 2014;80:175–83. Available from: https://doi.org/10.1016/j.ejmech.2014.04.050

  42. Sood S, Jain K, Gowthamarajan K. Curcumin-donepezil–loaded nanostructured lipid carriers for intranasal delivery in an Alzheimer’s disease model. Alzheimer’s Dement [Internet]. 2013 [cited 2016 Jan 9];9:P299. Available from: http://www.sciencedirect.com/science/article/pii/S1552526013012661

  43. Kakkar V, Muppu SK, Chopra K, Kaur IP. Curcumin loaded solid lipid nanoparticles: An efficient formulation approach for cerebral ischemic reperfusion injury in rats. Eur J Pharm Biopharm [Internet]. 2013;85:339–45. Available from: https://doi.org/10.1016/j.ejpb.2013.02.005

  44. Sugasini D, Lokesh BR. Prostaglandins , Leukotrienes and essential fatty acids Curcumin and linseed oil co-delivered in phospholipid nanoemulsions enhances the levels of docosahexaenoic acid in serum and tissue lipids of rats. Prostaglandins Leukot Essent Fat Acids [Internet]. Elsevier Ltd; 2017;119:45–52. Available from: https://doi.org/10.1016/j.plefa.2017.03.007

  45. Wu X, Xu J, Huang X, Wen C. Self-microemulsifying drug delivery system improves curcumin dissolution and bioavailability. Drug Dev Ind Pharm. 2011;37:15–23.

    Article  CAS  PubMed  Google Scholar 

  46. Bergonzi MC, Hamdouch R, Mazzacuva F, Isacchi B, Bilia AR. Optimization, characterization and in vitro evaluation of curcumin microemulsions. LWT - Food Sci Technol [Internet]. Elsevier Ltd; 2014;59:148–55. Available from: http://www.sciencedirect.com/science/article/pii/S0023643814003612

  47. Mathew A, Fukuda T, Nagaoka Y, Hasumura T, Morimoto H, Yoshida Y, et al. Curcumin loaded-PLGA nanoparticles conjugated with Tet-1 peptide for potential use in Alzheimer’s disease. PLoS One. 2012;7.

  48. Yin Y-M, Cui F-D, Mu C-F, Choi M-K, Kim JS, Chung S-J, et al. Docetaxel microemulsion for enhanced oral bioavailability: Preparation and in vitro and in vivo evaluation. J Control Release [Internet]. 2009 [cited 2017 Jul 21];140:86–94. Available from: http://linkinghub.elsevier.com/retrieve/pii/S0168365909005781

  49. Dahan A, Miller JM. The solubility-permeability interplay and its implications in formulation design and development for poorly soluble drugs. AAPS J. 2012;14:244–51.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Mathematical models of drug release. Strateg to modify drug release from pharm syst [Internet]. Elsevier; 2015. p. 63–86. Available from: https://linkinghub.elsevier.com/retrieve/pii/B9780081000922000059

  51. Maher S, Brayden DJ, Casettari L, Illum L. Application of permeation enhancers in oral delivery of macromolecules: An update. Pharmaceutics. 2019;11:1–23.

    Article  Google Scholar 

  52. Shinde, Rajshree L.; Jindal, Anil B.; Devarajan P V. Microemulsions and nanoemulsions for targeted drug delivery to the brain. Curr Nanosci. 2011;7:119–33.

  53. Hoosain FG, Choonara YE, Tomar LK, Kumar P, Tyagi C, Du Toit LC, et al. Bypassing p-glycoprotein drug efflux mechanisms: possible applications in pharmacoresistant schizophrenia therapy. Biomed Res Int. Hindawi Publishing Corporation; 2015;2015.

  54. Amin ML. P-glycoprotein inhibition for optimal drug delivery. Drug Target Insights. 2013;2013:27–34.

    Google Scholar 

  55. Alqahtani MS, Kazi M, Alsenaidy MA, Ahmad MZ. Advances in oral drug delivery. Front Pharmacol. 2021;12.

  56. Schinkel AH. P-Glycoprotein, a gatekeeper in the blood-brain barrier. Adv Drug Deliv Rev. 1999;36:179–94.

    Article  CAS  PubMed  Google Scholar 

  57. Van Assema DME, Lubberink M, Boellaard R, Schuit RC, Windhorst AD, Scheltens P, et al. P-glycoprotein function at the blood-brain barrier: Effects of age and gender. Mol Imaging Biol. 2012;14:771–6.

    Article  PubMed  PubMed Central  Google Scholar 

  58. Upadhyay RK. Drug delivery systems, CNS protection, and the blood brain barrier. Biomed Res Int. Hindawi Publishing Corporation; 2014;2014.

  59. Bellettato CM, Scarpa M. Possible strategies to cross the blood – brain barrier. Ital J Pediatr. 2018;44.

  60. Teleanu D, Chircov C, Grumezescu A, Volceanov A, Teleanu R. Blood-brain delivery methods using nanotechnology. Pharmaceutics [Internet]. 2018;10:269. Available from: http://www.mdpi.com/1999-4923/10/4/269

  61. Chatterjee B, Sengupta P, Tekade RK. Pharmacokinetic characterization of drugs and new product development. Biopharm Pharmacokinet Considerations Vol 1 Adv Pharm Prod Dev Res. Academic Press; 2021;195–277.

  62. Thakkar H, Nangesh J, Parmar M, Patel D. Formulation and characterization of lipid-based drug delivery system of raloxifene-microemulsion and self-microemulsifying drug delivery system. J Pharm Bioallied Sci. 2011;3:442–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. da Silva IF, Freitas-Lima LC, Graceli JB, Rodrigues LC de M. Organotins in neuronal damage, brain function, and behavior: A short review. Front Endocrinol (Lausanne). 2018;8:6–11.

  64. Corvino V, Marchese E, Michetti F, Geloso MC. Neuroprotective strategies in hippocampal neurodegeneration induced by the neurotoxicant trimethyltin. Neurochem Res. 2013;38:240–53.

    Article  CAS  PubMed  Google Scholar 

  65. Wang B, Ma L, Tao X, Lipsky PE. Triptolide, an active component of the Chinese herbal remedy Tripterygium wilfordii Hook F, inhibits production of nitric oxide by decreasing inducible nitric oxide synthase gene transcription. Arthritis Rheum. 2004;50:2995–3003.

    Article  CAS  PubMed  Google Scholar 

  66. Nirwane A, Sridhar V, Majumdar A. Neurobehavioural changes and brain oxidative stress induced by acute exposure to GSM900 mobile phone radiations in Zebrafish (Danio rerio). Toxicol Res. 2016;32:123–32.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Nunes ME, Müller TE, Braga MM, Fontana BD, Quadros VA, Marins A, et al. Chronic treatment with paraquat induces brain injury, changes in antioxidant defenses system, and modulates behavioral functions in zebrafish. Mol Neurobiol. 2017;54:3925–34.

    Article  CAS  PubMed  Google Scholar 

  68. De Carvalho TS, Cardoso PB, Santos-Silva M, Lima-Bastos S, Luz WL, Assad N, et al. Oxidative Stress Mediates Anxiety-Like Behavior Induced by High Caffeine Intake in Zebrafish: Protective Effect of Alpha-Tocopherol. Oxid Med Cell Longev. 2019;2019.

Download references

Acknowledgements

Authors are grateful to Arjuna Naturals, BASF India and Sahyadri Natural Extracts for providing gift samples. The authors also thank Dr. Piyush Mehta for his valuable technical assistance in writing the manuscript.

Funding

This research project was funded by All India Council for Technical Education (AICTE), Government of India under RPS-NDF Scheme (ref no. 8–33/RIFD/RPS-NDF/POLICY-1/2018–19).

Author information

Authors and Affiliations

Authors

Contributions

All the authors participated in research design and wrote or contributed to the writing of the manuscript; S.K.M. was responsible for Conceptualization, Methodology, Validation, Formal analysis, Investigation, Resources, Writing—Original Draft, Writing—Review & Editing, and Visualization. A.P.P. was responsible for Conceptualization, Resources, Writing—Review & Editing, Visualization, Supervision, Project administration and Funding acquisition.

Corresponding author

Correspondence to Atmaram Pawar.

Ethics declarations

Conflict of Interest

Authors declare that they have no conflict of interest.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

More, S., Pawar, A. Brain Targeted Curcumin Loaded Turmeric Oil Microemulsion Protects Against Trimethyltin Induced Neurodegeneration in Adult Zebrafish: A Pharmacokinetic and Pharmacodynamic Insight. Pharm Res 40, 675–687 (2023). https://doi.org/10.1007/s11095-022-03467-9

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11095-022-03467-9

Keywords

Navigation