Oral Delivery of Methylthioadenosine to the Brain Employing Solid Lipid Nanoparticles: Pharmacokinetic, Behavioral, and Histopathological Evidences


The present study aimed to orally deliver methylthioadenosine (MTA) to the brain employing solid lipid nanoparticles (SLNs) for the management of neurological conditions like multiple sclerosis. The stearic acid–based SLNs were below 100 nm with almost neutral zeta potential and offered higher drug entrapment and drug loading. Cuprizone-induced demyelination model in mice was employed to mimic the multiple sclerosis–like conditions. It was observed that the MTA-loaded SLNs were able to maintain the normal metabolism, locomotor activity, motor coordination, balancing, and grip strength of the rodents in substantially superior ways vis-à-vis plain MTA. Histopathological studies of the corpus callosum and its subsequent staining with myelin staining dye luxol fast blue proved the potential of MTA-loaded SLNs in the remyelination of neurons. The pharmacokinetic studies provided the evidences for improved bioavailability and enhanced bioresidence supporting the pharmacodynamic findings. The studies proved that SLN-encapsulated MTA can be substantially delivered to the brain and can effectively remyelinate the neurons. It can reverse the multiple sclerosis–like symptoms in a safer and effective manner, that too by oral route.

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

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


  1. 1.

    Warren S, Warren KG. Multiple sclerosis. Malta: World Health Organization; 2001.

    Google Scholar 

  2. 2.

    Kumar P, Sharma G, Gupta V, Kaur R, Thakur K, Malik R, et al. Preclinical explorative assessment of dimethyl fumarate-based biocompatible nanolipoidal carriers for the management of multiple sclerosis. ACS Chem Neurosci. 2018;9:1152–8. https://doi.org/10.1021/acschemneuro.7b00519.

    CAS  Article  PubMed  Google Scholar 

  3. 3.

    Pandit L, Murthy JMK. Treatment of multiple sclerosis. Ann Indian Acad Neurol. 2011;14:S65–9.

    Article  Google Scholar 

  4. 4.

    Moreno B, Fernandez-Diez B, Di Penta A, Villoslada P. Preclinical studies of methylthioadenosine for the treatment of multiple sclerosis. Mult Scler. 2010;16:1102–8. https://doi.org/10.1177/1352458510375968.

    CAS  Article  PubMed  Google Scholar 

  5. 5.

    Moreno B, Vila G, Fernandez-Diez B, Vázquez R, Penta A, Errea O, et al. Methylthioadenosine promotes remyelination by inducing oligodendrocyte differentiation. Mult Scler Demyelinating Disord. 2017;2:1–13. https://doi.org/10.1186/s40893-017-0020-8.

    Article  Google Scholar 

  6. 6.

    Kumar P, Sharma G, Kumar R, Malik R, Singh B, Katare OP, et al. Stearic acid based, systematically designed oral lipid nanoparticles for enhanced brain delivery of dimethyl fumarate. Nanomedicine (Lond). 2017;12:2607–21. https://doi.org/10.2217/nnm-2017-0082.

    CAS  Article  Google Scholar 

  7. 7.

    Kumar P, Sharma G, Kumar R, Malik R, Singh B, Katare OP, et al. Vitamin-derived nanolipoidal carriers for brain delivery of dimethyl fumarate: a novel approach with preclinical evidence. ACS Chem Neurosci. 2017;8:1390–6. https://doi.org/10.1021/acschemneuro.7b00041.

    CAS  Article  PubMed  Google Scholar 

  8. 8.

    Kumar P, Sharma G, Kumar R, Malik R, Singh B, Katare OP, et al. Enhanced brain delivery of dimethyl fumarate employing tocopherol-acetate-based nanolipidic carriers: evidence from pharmacokinetic, biodistribution, and cellular uptake studies. ACS Chem Neurosci. 2017;8:860–5. https://doi.org/10.1021/acschemneuro.6b00428.

    CAS  Article  PubMed  Google Scholar 

  9. 9.

    Kumar P, Sharma G, Kumar R, Singh B, Malik R, Katare OP, et al. Promises of a biocompatible nanocarrier in improved brain delivery of quercetin: biochemical, pharmacokinetic and biodistribution evidences. Int J Pharm. 2016;515:307–14. https://doi.org/10.1016/j.ijpharm.2016.10.024.

    CAS  Article  PubMed  Google Scholar 

  10. 10.

    Raza K, Singh B, Lohan S, Sharma G, Negi P, Yachha Y, et al. Nano-lipoidal carriers of tretinoin with enhanced percutaneous absorption, photostability, biocompatibility and anti-psoriatic activity. Int J Pharm. 2013;456:65–72. https://doi.org/10.1016/j.ijpharm.2013.08.019.

    CAS  Article  PubMed  Google Scholar 

  11. 11.

    Raza K, Singh B, Singal P, Wadhwa S, Katare OP. Systematically optimized biocompatible isotretinoin-loaded solid lipid nanoparticles (SLNs) for topical treatment of acne. Colloids Surf B Biointerfaces. 2013;105:67–74. https://doi.org/10.1016/j.colsurfb.2012.12.043.

    CAS  Article  PubMed  Google Scholar 

  12. 12.

    Zhen W, Liu A, Lu J, Zhang W, Tattersall D, Wang J. An alternative cuprizone-induced demyelination and remyelination mouse model. ASN Neuro. 2017;9(4):1759091417725174. https://doi.org/10.1177/1759091417725174.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  13. 13.

    Kumar P, Kalonia H, Kumar A. Possible GABAergic mechanism in the neuroprotective effect of gabapentin and lamotrigine against 3-nitropropionic acid induced neurotoxicity. Eur J Pharmacol. 2012;674:265–74.

    CAS  Article  Google Scholar 

  14. 14.

    Tung VW, Burton TJ, Quail SL, Mathews MA, Camp AJ. Motor performance is impaired following vestibular stimulation in ageing mice. Front Aging Neurosci. 2016;8:12. https://doi.org/10.3389/fnagi.2016.00012.

    Article  PubMed  PubMed Central  Google Scholar 

  15. 15.

    Franco-Pons N, Torrente M, Colomina MT, Vilella E. Behavioral deficits in the cuprizone-induced murine model of demyelination/remyelination. Toxicol Lett. 2007;169:205–13.

    CAS  Article  Google Scholar 

  16. 16.

    Matsushima GK, Morell P. The neurotoxicant, cuprizone, as a model to study demyelination and remyelination in the central nervous system. Brain Pathol 2001;11:107–116.

  17. 17.

    Masserini M. Nanoparticles for brain drug delivery. ISRN Biochem. 2013;Article ID 238428, 18 pages. https://doi.org/10.1155/2013/238428.

  18. 18.

    Kumar M, Sharma G, Kumar R, Singh B, Katare OP, Raza K. Lysine-based C60-fullerene nanoconjugates for monomethyl fumarate delivery: a novel nanomedicine for brain cancer cells. ACS Biomater Sci Eng. 2018;4(6):2134–42.

    CAS  Article  Google Scholar 

  19. 19.

    Raza K, Negi P, Takyar S, Shukla A, Amarji B, Katare OP. Novel dithranol phospholipid microemulsion for topical application: development, characterization and percutaneous absorption studies. J Microencapsul. 2011;28(3):190–9. https://doi.org/10.3109/02652048.2010.546435.

    CAS  Article  PubMed  Google Scholar 

  20. 20.

    Raza K, Kumar P, Kumar N, Malik R. Pharmacokinetics and biodistribution of the nanoparticles. In Advances in nanomedicine for the delivery of therapeutic nucleic acids 2017 (pp. 165–186).

  21. 21.

    Zendedel A, Beyer C, Kipp M. Cuprizone induced demyelination as a tool to study remyelination and axonal protection. J Mol Neurosci. 51:567–72.

Download references


The financial support from the Central University of Rajasthan, Bandar Sindri, Distt., Ajmer, India, is duly acknowledged.

Author information



Corresponding author

Correspondence to Kaisar Raza.

Ethics declarations

All the animal protocols were duly approved by the Animal Ethics Committee, Panjab University, Chandigarh, and the studies were performed in strict accordance to the guidelines laid by the University in accordance with the apt national regulations.

Conflict of Interest

The 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.

Guest Editor: Sanyog Jain

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Kumar, P., Sharma, G., Gupta, V. et al. Oral Delivery of Methylthioadenosine to the Brain Employing Solid Lipid Nanoparticles: Pharmacokinetic, Behavioral, and Histopathological Evidences. AAPS PharmSciTech 20, 74 (2019). https://doi.org/10.1208/s12249-019-1296-0

Download citation


  • multiple sclerosis
  • brain delivery
  • lipid-based systems
  • remyelination
  • safety