Skip to main content

Advertisement

SpringerLink
Log in

A Preliminary Pharmacodynamic Study for the Management of Alzheimer’s Disease Using Memantine-Loaded PLGA Nanoparticles

  • Research Article
  • Published:
AAPS PharmSciTech Aims and scope Submit manuscript

Abstract

Alzheimer’s disease is becoming a common disorder of the elderly population due to shrinkage of the brain size with age and many other neurological complications. To provide an effective treatment option, memantine-encapsulated polymeric nanoparticles were prepared in the study. The nanoparticles were prepared by using nanoprecipitation followed by homogenization and ultrasonication methods, characterized on the basis of particle size, polydispersity index, and zeta potential. Further, in vitro release profile, cytotoxicity analysis, and Giemsa staining were conducted. To observe the efficacy of nanoparticles in scopolamine-induced Alzheimer models in vivo studies were also carried out. The results showed that nanoparticles were in the nano range with a particle size of 58.04 nm and − 23 mV zeta potential. The in vitro release was also sustained till 24 h with ~ 100% release in selected media phosphate buffer saline, simulated nasal fluid, and artificial cerebrospinal fluid. The cytotoxicity results with ~ 98 to 100% cell viability and no morphological changes through Giemsa staining indicated that nanoparticles were not leading to cell toxicity. The gamma scintigraphy studies showed higher uptake of the drug in the target site through the intranasal route and pharmacodynamic studies indicated that nanoparticles were able to inhibit the spatial memory impairment significantly as compared to the control group. The findings clearly indicated that the developed memantine nanoparticles could act as an alternative approach for the management of Alzheimer’s disease.

Graphical Abstract

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

Access this article

Log in via an institution

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

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8
Fig. 9

Similar content being viewed by others

References

  1. Hao Y, Xiong R, Gong X. Memantine, NMDA receptor antagonist, attenuates ox-LDL-induced inflammation and oxidative stress via activation of BDNF/TrkB signaling pathway in HUVECs. Inflammation. 2021;44(2):659–70.

    Article  CAS  PubMed  Google Scholar 

  2. Moriguchi S, Inagaki R, Fukunaga K. Memantine improves cognitive deficits via KATP channel inhibition in olfactory bulbectomized mice. Mole Cell Neurosci. 2021;117: 103680.

    Article  CAS  Google Scholar 

  3. Robinson DM, Keating GM. Memantine Drugs. 2006;66(11):1515–34.

    Article  CAS  PubMed  Google Scholar 

  4. Zhang W, Kandel N, Zhou Y, Smith N, Ferreira BC, Perez M, Claure ML, Mintz KJ, Wang C, Leblanc RM. Drug delivery of memantine with carbon dots for Alzheimer’s disease: blood–brain barrier penetration and inhibition of tau aggregation. J Colloid Interf Sci. 2022;617:20–31.

    Article  CAS  Google Scholar 

  5. Gothwal A, Kumar H, Nakhate KT, Ajazuddin Dutta A, Borah A, Gupta U. Lactoferrin coupled lower generation PAMAM dendrimers for brain targeted delivery of memantine in aluminum-chloride-induced Alzheimer’s disease in mice. Bioconjug chem. 2019;30(10):2573–83.

    Article  CAS  PubMed  Google Scholar 

  6. Kaur A, Nigam K, Srivastava S, Tyagi A, Dang S. Memantine nanoemulsion: a new approach to treat Alzheimer’s disease. J Microencapsul. 2020;37(5):355–65.

    Article  CAS  PubMed  Google Scholar 

  7. Abd Razak M, Julianto T, Majeed ABA. Enhancement of memantine uptake in the brain by incorporation with nanoparticles and given intranasally. IBRO Reports. 2019;6:S169.

    Article  Google Scholar 

  8. Vos PJ, Kuijt N, Kaya M, Rol S, van der Maaden K. Nanoporous microneedle arrays seamlessly connected to a drug reservoir for tunable transdermal delivery of memantine. Eur J Pharm Sci. 2020;150: 105331.

    Article  CAS  PubMed  Google Scholar 

  9. Hans ML, Lowman AM. Biodegradable nanoparticles for drug delivery and targeting. Curr Opin Solid State Mater Sci. 2002;6(4):319–27.

    Article  CAS  Google Scholar 

  10. Mitchell MJ, Billingsley MM, Haley RM, Wechsler ME, Peppas NA, Langer R. Engineering precision nanoparticles for drug delivery. Nat Rev Drug Discov. 2021;20(2):101–24.

    Article  CAS  PubMed  Google Scholar 

  11. Sahni JK, Doggui S, Ali J, Baboota S, Dao L, Ramassamy C. Neurotherapeutic applications of nanoparticles in Alzheimer’s disease. J Control Release. 2011;152(2):208–31.

    Article  CAS  PubMed  Google Scholar 

  12. Wilson B, Samanta MK, Santhi K, Kumar KS, Ramasamy M, Suresh B. Chitosan nanoparticles as a new delivery system for the anti-Alzheimer drug tacrine. Nanomed Nanotechnol Biol Med. 2010;6(1):144–52.

    Article  CAS  Google Scholar 

  13. Keller LA, Merkel O, Popp A. Intranasal drug delivery: opportunities and toxicologic challenges during drug development. Drug Deliv Transl Res. 2021;12:735–57.

    Article  PubMed  PubMed Central  Google Scholar 

  14. Fonseca LC, Lopes JA, Vieira J, Viegas C, Oliveira CS, Hartmann RP, Fonte P. Intranasal drug delivery for treatment of Alzheimer’s disease. Drug Deliv Transl Res. 2021;11(2):411–25.

    Article  PubMed  Google Scholar 

  15. Nigam K, Kaur A, Tyagi A, Nematullah M, Khan F, Gabrani R, Dang S. Nose-to-brain delivery of lamotrigine-loaded PLGA nanoparticles. Drug Deliv Transl Res. 2019;9(5):879–90.

    Article  CAS  PubMed  Google Scholar 

  16. Kaur A, Nigam K, Bhatnagar I, Sukhpal H, Awasthy S, Shankar S, Tyagi A, Dang S. Treatment of Alzheimer’s diseases using donepezil nanoemulsion: an intranasal approach. Drug Deliv Transl Res. 2020;10(6):1862–75.

    Article  CAS  PubMed  Google Scholar 

  17. Nigam K, Kaur A, Tyagi A, Manda K, Gabrani R, Dang S. Baclofen-loaded poly (d, l-lactide-co-glycolic acid) nanoparticles for neuropathic pain management: in vitro and in vivo evaluation. Rejuvenation Res. 2019;22(3):235–45.

    Article  CAS  PubMed  Google Scholar 

  18. Shah P, Sarolia J, Vyas B, Wagh P, Ankur K, Kumar MA. PLGA nanoparticles for nose to brain delivery of Clonazepam: formulation, optimization by 32 Factorial design, in vitro and in vivo evaluation. Curr Drug Deliv. 2021;18(6):805–24.

    Article  CAS  PubMed  Google Scholar 

  19. Sobczak A, Muszalska I, Rohowska P, Inerowicz T, Dotka H, Jelińska A. Determination of adamantane derivatives in pharmaceutical formulations by using spectrophotometric UV-Vis method. Drug Dev Ind Pharm. 2013;39(5):657–61.

    Article  CAS  PubMed  Google Scholar 

  20. Chalikwar SS, Mene BS, Pardeshi CV, Belgamwar VS, Surana SJ. Self-assembled, chitosan grafted PLGA nanoparticles for intranasal delivery: design, development and ex vivo characterization. Polym Plast Technol Eng. 2013;52(4):368–80.

    Article  CAS  Google Scholar 

  21. Liu MY, Meng SN, Wu HZ, Wang S, Wei MJ. Pharmacokinetics of single-dose and multiple-dose memantine in healthy chinese volunteers using an analytic method of liquid chromatography-tandem mass spectrometry. Clin Ther. 2008;30(4):641–53.

    Article  CAS  PubMed  Google Scholar 

  22. Md S, Ali M, Baboota S, Sahni JK, Bhatnagar A, Ali J. Preparation, characterization, in vivo biodistribution and pharmacokinetic studies of donepezil-loaded PLGA nanoparticles for brain targeting. Drug Dev Ind Pharm. 2014;40(2):278–87.

  23. Kumar M, Misra A, Babbar AK, Mishra AK, Mishra P, Pathak K. Intranasal nanoemulsion based brain targeting drug delivery system of risperidone. Int J Pharm. 2008;358(1–2):285–91.

    Article  CAS  PubMed  Google Scholar 

  24. Drachman DA, Leavitt J. Human memory and the cholinergic system: a relationship to aging? Arch Neurol. 1974;30(2):113–21.

    Article  CAS  PubMed  Google Scholar 

  25. Bali ZK, Bruszt N, Tadepalli SA, Csurgyók R, Nagy LV, Tompa M, Hernádi I. Cognitive enhancer effects of low memantine doses are facilitated by an alpha7 nicotinic acetylcholine receptor agonist in scopolamine-induced amnesia in rats. Front Pharmacol. 2019;10:73.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Flicker C, Serby M, Ferris SH. Scopolamine effects on memory, language, visuospatial praxis and psychomotor speed. Psychopharmacology. 1990;100(2):243–50.

    Article  CAS  PubMed  Google Scholar 

  27. Salatin S, Barar J, Barzegar-Jalali M, Adibkia K, Kiafar F, Jelvehgari M. An alternative approach for improved entrapment efficiency of hydrophilic drug substance in PLGA nanoparticles by interfacial polymer deposition following solvent displacement. Jundishapur J Nat Pharml Prod. 2018;13(4): e12873.

    CAS  Google Scholar 

  28. Battaglia L, Panciani PP, Muntoni E, Capucchio MT, Biasibetti E, De Bonis P, Swaminathan S. Lipid nanoparticles for intranasal administration: application to nose-to-brain delivery. Expert Opin Drug Deliv. 2018;15(4):369–78.

    Article  CAS  PubMed  Google Scholar 

  29. Nunez J. Morris water maze experiment JoVE. 2008;19: e897.

    Google Scholar 

  30. Honary S, Zahir F. Effect of zeta potential on the properties of nano-drug delivery systems - a review (Part 1). Trop J Pharm Res. 2013;12(2):265–73.

    Google Scholar 

  31. Panyam J, Labhasetwar V. Biodegradable nano-particles for drug and gene delivery to cells and tissue. Adv Drug Deliv Rev. 2003;55(3):329–47.

    Article  CAS  PubMed  Google Scholar 

  32. Wenk GL. Assessment of spatial memory using the radial arm maze and Morris water maze. Curr Protoc Neurosci. 2004; Chapter 8: Unit:8.5A

  33. Burilova EA, Pashirova T, Zueva IV, Gibadullina E, Lushchekina SV, Sapunova A, Sinyashin OG. Bi-functional sterically hindered phenol lipid-based delivery systems as potential multi-target agents against Alzheimer’s disease via intranasal route. Nanoscale. 2020;12(25):13757–70.

    Article  CAS  PubMed  Google Scholar 

  34. Sathya S, Manogari BG, Thamaraiselvi K, Vaidevi S, Ruckmani K, Devi KP. Phytol loaded PLGA nanoparticles ameliorate scopolamine-induced cognitive dysfunction by attenuating cholinesterase activity, oxidative stress and apoptosis in Wistar rat. Nutr Neurosci. 2020;25(3):485–501.

    Article  PubMed  Google Scholar 

Download references

Acknowledgements

We are thankful to the Jaypee Institute of Information Technology, Noida, and INMAS, DRDO, New Delhi for providing basic infrastructural support to complete this work.

Funding

The authors are thankful to the Department of Biotechnology, Ministry of Sciences, New Delhi for providing financial support to complete this study under BioCare Women Scientist Scheme (DBT Grant No. BT/PR19580/BIC/101/865/2016).

Author information

Authors and Affiliations

  1. Department of Biotechnology, Jaypee Institute of Information Technology, A-10, Sector 62, Noida, UP, 201307, India

    Atinderpal Kaur, Kuldeep Nigam & Shweta Dang

  2. Division of CBRN Defense, Institute of Nuclear Medicine and Allied Sciences, Brig SK Mazumdar Marg, Delhi, 110054, India

    Amit Tyagi

Authors
  1. Atinderpal Kaur
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Kuldeep Nigam
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Amit Tyagi
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Shweta Dang
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

All authors have contributed significantly in the completion of this manuscript. Following are the details about the contribution of each author:

Atinderpal Kaur—The first author performed all the experimental work for the manuscript, interpreted the data, and drafted the manuscript.

Kuldeep Nigam—The second author helped in the completion of cytotoxicity analysis and animal studies.

Amit Tyagi—The author supervised and provided his timely guidance to the first author in carrying out pharmacokinetic studies.

Shweta Dang—The corresponding author was the mentor of the project and provide her guidance and supervised all the experimental work carried out by the first author for the development of the current manuscript.

Corresponding author

Correspondence to Shweta Dang.

Ethics declarations

Ethics Approval

All the animal experiments were approved by the ethical committee of Institute of Nuclear Medicine and Allied Sciences (INMAS) Institutional Animal Ethics Committee (IAEC), New Delhi, India, vide number INM/IAEC/16/10.

Conflict of Interest

The authors declare no competing interests.

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

Kaur, A., Nigam, K., Tyagi, A. et al. A Preliminary Pharmacodynamic Study for the Management of Alzheimer’s Disease Using Memantine-Loaded PLGA Nanoparticles. AAPS PharmSciTech 23, 298 (2022). https://doi.org/10.1208/s12249-022-02449-9

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1208/s12249-022-02449-9

Keywords

Search

Navigation