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Nicotinamide loaded functionalized solid lipid nanoparticles improves cognition in Alzheimer’s disease animal model by reducing Tau hyperphosphorylation

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Abstract

Background

Nicotinamide is considered to be effective in halting the Alzheimer’s disease progression. The body could absorb a limited amount of nicotinamide at a time, requiring multiple doses through a day. To overcome such an obstacle which reduces the patient compliance, a sustained/controlled delivery system could be useful.

Method

Nicotinamide loaded solid lipid nanoparticles (SLN) were prepared and functionalized with polysorbate 80 (S80), phosphatidylserine (PS) or phosphatidic acid (PA). The acquired particles were characterized and evaluated in respect of their cytotoxicity, biodistribution, and in vivo effectiveness through the different routes of administration.

Results

The optimum sizes of 112 ± 1.6 nm, 124 ± 0.8 nm, and 137 ± 1.05 nm were acquired for S80-, PS-, and PA-functionalized SLNs, respectively. The in vitro cytotoxicity on SH-SY5Y cell line showed the safety of formulations except for S80-functionalized SLNs. Biodistribution study of SLNs has proved the benefits of functionalization in improving the brain delivery. The results of spatial and memory test, i.e. Morris water maze, and also histopathology and biochemical tests demonstrated the effectiveness of i.p. injection of PS -functionalized SLNs in improving the cognition, preserving the neuronal cells and reducing tau hyperphosphorylation in a rat model of Alzheimer’s disease.

Conclusion

The acquired PS-functionalized SLN could be a potential brain delivery system. Loaded with nicotinamide, an HDAC inhibitor, it could ameliorate the cognition impairment of rats more effectively than the conventional administration of nicotinamide, i.e. oral, in the early stage of Alzheimer’s disease.

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References

  1. Grabowski, T.J., Clinical features and diagnosis of Alzheimer disease. 2015: www.uptodate.com.

  2. Bateman RJ, Xiong C, Benzinger TLS, Fagan AM, Goate A, Fox NC, et al. Clinical and biomarker changes in dominantly inherited Alzheimer’s disease. N Engl J Med. 2012;367(9):795–804.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Banks WA. Drug delivery to the brain in Alzheimer's disease: consideration of the blood–brain barrier. Adv Drug Deliv Rev. 2012;64:629–39.

    Article  CAS  PubMed  Google Scholar 

  4. Teunissen, C.E. and T.J.M.V.D. Cammen, Alzheimer’s Disease, In Protein Misfolding in Neurodegenerative Diseases - Mechanisms and Therapeutic Strategies H.J. Smith, C. Simons, and R.D.E. Sewell, editors. 2008, CRC Press, Boca Raton.

  5. Huang Y, Mucke L. Alzheimer mechanisms and therapeutic strategies. Cell. 2012;148:1204–22.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Spires-Jones TL, Stoothoff WH, de Calignon A, Jones PB, Hyman BT. Tau pathophysiology in neurodegeneration: a tangled issue. Trends Neurosci. 2009;32(3):150–9.

    Article  CAS  PubMed  Google Scholar 

  7. Lindwall G, Cole RD. Phosphorylation affects the ability of tau protein to promote microtubule assembly. J Biol Chem. 1984;259(8):5301–5.

    CAS  PubMed  Google Scholar 

  8. Harrington CR. The aetiology of Alzheimer's disease: diverse routes into a common Tau PathwayI. Aluminium and Alzheimer's disease; The science that describes the link. In: Exley C, Editor. 2001. p. 97–132.

  9. Durham B. Novel histone deacetylase (HDAC) inhibitors with improved selectivity for HDAC2 and 3 protect against neural cell death. Biosci Horiz. 2012;5. https://doi.org/10.1093/biohorizons/hzs003.

    CAS  Google Scholar 

  10. Bardai FH, D’Mello SR. Selective toxicity by HDAC3 in neurons: regulation by Akt and GSK3β. J Neurosci. 2011;31(5):1746–51.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Saha R, Pahan K. HATs and HDACs in neurodegeneration: a tale of disconcerted acetylation homeostasis. Cell Death Differ. 2006;13(4):539–50.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Stilling RM, Fischer A. The role of histone acetylation in age-associated memory impairment and Alzheimer’s disease. Neurobiol Learn Mem. 2011;96(1):19–26.

    Article  CAS  PubMed  Google Scholar 

  13. Timmermann S, Lehrmann H, Polesskaya A, Harel-Bellan A. Histone acetylation and disease. Cell Mol Life Sci. 2001;58(5–6):728–36.

    Article  CAS  PubMed  Google Scholar 

  14. Roth S, Denu J, Allis C. Histone acetyltransferases. Annu Rev Biochem. 2001;70:81–120.

    Article  CAS  Google Scholar 

  15. Haberland M, Montgomery RL, Olson EN. The many roles of histone deacetylases in development and physiology: implications for disease and therapy. Nat Rev Genet. 2009;10(1):32–42.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Peixoto L, Abel T. The role of histone acetylation in memory formation and cognitive impairments. Neuropsychopharmacology. 2013;38(1):62–76.

    Article  CAS  PubMed  Google Scholar 

  17. Grill J, Irvine UOC. Nicotinamide as an Early Alzheimer's Disease Treatment (NEAT). 2017, ClinicalTrials.gov - Identifier: NCT03061474.

  18. Fillit H et al. Closing in on a cure - 2017 Alzheimer’s clinical trials report. Alzheimer drug Discovery Foundation, 2017. https://www.alzdiscovery.org/research-and-grants/clinical-trials-report/closing-in-on-a-cure-2017

  19. Schreiber S, Irvine UOC. Safety study of nicotinamide to treat Alzheimer's disease. 2007, ClinicalTrials.gov - Identifier: NCT00580931.

  20. Prousky JE. The use of Niacinamide and Solanaceae (nightshade) elimination in the treatment of osteoarthritis. J Orthomol Med. 2015;30(1):13–21.

    Google Scholar 

  21. Green K, et al. Nicotinamide restores cognition in Alzheimer’s disease transgenic mice via a mechanism involving Sirtuin inhibition and selective reduction of Thr231-Phosphotau. J Neurosci. 2008;28(45):11500–10.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Knip M, Douek IF, Moore WPT, Gillmor HA, McLean AEM, Bingley PJ, et al. Safety of high-dose nicotinamide: a review. Diabetologia. 2000;43:1337–45.

    Article  CAS  PubMed  Google Scholar 

  23. Müller RH, Mäder K, Gohla S. Solid lipid nanoparticles (SLN) for controlled drug delivery – a review of the state of the art. Eur J Pharm Biopharm. 2000;50(1):161–77.

    Article  PubMed  Google Scholar 

  24. Blasi P, et al. Solid lipid nanoparticles for targeted brain drug delivery. Adv Drug Deliv Rev. 2007;59(6):454–77.

    Article  CAS  PubMed  Google Scholar 

  25. Kaur IP, Bhandari R, Bhandari S, Kakkar V. Potential of solid lipid nanoparticles in brain targeting. J Control Release. 2008;127(2):97–109.

    Article  CAS  PubMed  Google Scholar 

  26. Mozzi R, Buratta S, Goracci G. Metabolism and functions of phosphatidylserine in mammalian brain. Neurochem Res. 2003;28(2):195–214.

    Article  CAS  PubMed  Google Scholar 

  27. Kim H-Y, Huang BX, Spector AA. Phosphatidylserine in the brain: metabolism and function. Prog Lipid Res. 2014;56:1–18.

    Article  CAS  PubMed  Google Scholar 

  28. Cunnane SC, Schneider JA, Tangney C, Tremblay-Mercier J, Fortier M, Bennett DA, et al. Plasma and brain fatty acid profiles in mild cognitive impairment and Alzheimer’s disease. J Alzheimers Dis. 2012;29(3):691–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Schutters K, Reutelingsperger C. Phosphatidylserine targeting for diagnosis and treatment of human diseases. Apoptosis. 2010;15:1072–82.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Sakai M, Yamatoya H, Kudo S. Pharmacological effects of phosphatidylserine enzymatically synthesized from soybean lecithin on brain functions in rodents. J Nutr Sci Vitaminol (Tokyo). 1996;42(1):47–54.

    Article  CAS  Google Scholar 

  31. Kidd PM. Phosphatidylserine; Membrane Nutrient for Memory. A clinical and mechanistic assessment. Altern Med Rev. 1996;1(2):70–84.

    Google Scholar 

  32. Vakilinezhad MA, Tanha S, Montaseri H, Dinarvand R, Azadi A, Akbari Javar H. Application of response surface method for preparation, optimization, and characterization of nicotinamide loaded solid lipid nanoparticles. Adv Pharm Bull. 2018;8(2):245–56.

    Article  PubMed  PubMed Central  Google Scholar 

  33. Gobbi M, Re F, Canovi M, Beeg M, Gregori M, Sesana S, et al. Lipid-based nanoparticles with high binding affinity for amyloid-b1-42 peptide. Biomaterials. 2010;31:6519–29.

    Article  CAS  PubMed  Google Scholar 

  34. Sharma G, Modgil A, Layek B, Arora K, Sun C, Law B, et al. Cell penetrating peptide tethered bi-ligand liposomes for delivery to brain in vivo: biodistribution and transfection. J Control Release. 2013;167(1):1–10.

    Article  CAS  PubMed  Google Scholar 

  35. Wen Z, Yan Z, He R, Pang Z, Guo L, Qian Y, et al. Brain targeting and toxicity study of odorranalectin-conjugated nanoparticles following intranasal administration. Drug Deliv. 2011;18(8):555–61.

    Article  CAS  PubMed  Google Scholar 

  36. Kosaraju J, Madhunapantula SRV, Chinni S, Khatwal RB, Dubala A, Muthureddy Nataraj SK, et al. Dipeptidyl peptidase-4 inhibition by Pterocarpus marsupium and Eugenia jambolana ameliorates streptozotocin induced Alzheimer’s disease. Behav Brain Res. 2014;267:55–65.

    Article  CAS  PubMed  Google Scholar 

  37. Liu P, Zou LB, Wang LH, Jiao Q, Chi TY, Ji XF, et al. Xanthoceraside attenuates tau hyperphosphorylation and cognitive deficits in intracerebroventricular-streptozotocin injected rats. Psychopharmacology. 2014;231(2):345–56.

    Article  CAS  PubMed  Google Scholar 

  38. Kamalinia G, Khodagholi F, Atyabi F, Amini M, Shaerzadeh F, Sharifzadeh M, et al. Enhanced brain delivery of deferasirox-lactoferrin conjugates for iron chelation therapy in neurodegenerative disorders: in vitro and in vivo studies. Mol Pharm. 2013;10(12):4418–31.

    Article  CAS  PubMed  Google Scholar 

  39. Grieb P. Intracerebroventricular Streptozotocin injections as a model of Alzheimer’s disease: in search of a relevant mechanism. Mol Neurobiol. 2016;53(3):1741–1752. https://doi.org/10.1007/s12035-015-9132-3.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Nazem A et al. Rodent models of neuroinflammation for Alzheimer’s disease. J Neuroinflamation. 2015;12(74). https://doi.org/10.1186/s12974-015-0291-y.

  41. Lecanu L, Papadopoulos V. Modeling Alzheimer’s disease with non-transgenic rat models. Alzheimers Res Ther. 2013;5(3):17.

    PubMed  PubMed Central  Google Scholar 

  42. Kamat PK. Streptozotocin induced Alzheimer’s disease like changes and the underlying neural degeneration and regeneration mechanism. Neural Regen Res. 2015;10(7):1050–2.

    Article  PubMed  PubMed Central  Google Scholar 

  43. Agrawal R, Tyagi E, Shukla R, Nath C. A study of brain insulin receptors, AChE activity and oxidative stress in rat model of ICV STZ induced dementia. Neuropharmacology. 2009;56:779–87.

    Article  CAS  PubMed  Google Scholar 

  44. D’Hooge R, Deyn PPD. Applications of the Morris water maze in the study of learning and memory. Brain Res Brain Res Rev. 2001;36:60–90.

    Article  PubMed  Google Scholar 

Download references

Acknowledgments

Authors would like to acknowledge Dr. Ali-Mohammad Tamaddon from the School of Pharmacy and Research Center for Nanotechnology in Drug Delivery, Shiraz University of Medical Sciences for his consult and cooperation throughout the study.

Funding

This study is part of Ph.D. thesis supported by Tehran University of Medical Sciences (TUMS); Grant no. 94–02–33-29374.

Author information

Authors and Affiliations

  1. Department of Pharmaceutics, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran

    Molood Alsadat Vakilinezhad & Hamid Akbari Javar

  2. Department of Pharmaceutical Biomaterials and Medical Biomaterials Research Center, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran

    Azadeh Amini

  3. Department of Pharmacology, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran

    Batool Faegheh Baha’addini Beigi Zarandi

  4. Department of Quality control, Faculty of Pharmacy, Shiraz University of Medical Sciences, Shiraz, Iran

    Hashem Montaseri

  5. Nanotechnology Research Center, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran

    Rassoul Dinarvand

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  1. Molood Alsadat Vakilinezhad
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Correspondence to Rassoul Dinarvand.

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Vakilinezhad, M.A., Amini, A., Akbari Javar, H. et al. Nicotinamide loaded functionalized solid lipid nanoparticles improves cognition in Alzheimer’s disease animal model by reducing Tau hyperphosphorylation. DARU J Pharm Sci 26, 165–177 (2018). https://doi.org/10.1007/s40199-018-0221-5

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