Pharmaceutical Research

, Volume 34, Issue 2, pp 492–505 | Cite as

In Vitro Modulation of TrkB Receptor Signaling upon Sequential Delivery of Curcumin-DHA Loaded Carriers Towards Promoting Neuronal Survival

  • Luis P. B. Guerzoni
  • Valérie Nicolas
  • Angelina Angelova
Research Paper



To in vitro investigate the capacity of carrier-free and lipid-nanoparticle (NP)-encapsulated phytochemical compounds to prevent neuronal damage through neurotrophin potentiating activities. Delivery of molecules promoting the neurotrophin receptor signaling in the central nervous system (CNS) present ongoing interest for combination therapy development.


Super-resolution Stimulated Emission Depletion (STED) microscopy imaging and flow cytometry analysis were employed to study the expression of the neurotrophin TrkB receptor in a neuronal cell model, which is highly responsive to binding of brain-derived neurotrophic factor (BDNF). Dual drug-loaded nanoparticle formulations, prepared by self-assembly of lyotropic lipids and PEGylated amphiphile derivatives, were delivered to differentiated human neuroblastoma SH-SY5Y cells subjected to degenerative conditions.


The expression of BDNF in the intra and extracellular domains was quantified by ELISA and flow cytometry after sequential treatment of the degenerating SH-SY5Y cells by neurotherapeutic formulations. Flow cytometry was also used to assess the phosphorylation of the transcription factor cAMP response element-binding protein (CREB) in the intracellular domain as a result of the treatment by nanoformulations.


Over time, dual drug formulations (curcumin and docosahexaenoic acid (DHA)) promoted the neuronal survival and repair processes through enhanced BDNF secretion and increased phosphorylation of CREB as compared to untreated degenerating cells.


BDNF CREB transcription factor curcumin DHA multidrug formulations 



Alzheimer’s disease




Brain-derived neurotrophic factor


Central nervous system


cAMP response element-binding protein


Docosahexaenoic acid


Enzyme-linked immunosorbent assay


Huntington’s disease


Mitogen activated protein kinase




Neutrotrophic factor


Phosphate buffered saline


Parkinson’s disease


Phosphatidylinositol-3 (PI3) kinase


Retinoic acid


Stimulated emission depletion

Trk receptor

Tropomyosin-related kinase receptor.



The platform MIPSIT of the Paris-Saclay Institute of Therapeutic Innovation is acknowledged for facilities in super resolution STED and laser confocal imaging. L.G. thanks the European Commission for granting a fellowship through the SERP-Chem Erasmus Mundus program, Dr. S. Lesieur for admission in the lab, E. Millart and Dr. V. Faivre for advices in utilization of the high-pressure homogeneizer, and Dr. Rosana Simon for valuable help in flow cytometry technique. A.A. acknowledges financial support from ANR SIMI10 Nanosciences and Dr. S. Denis and Dr. J. Vergnaud-Gauduchon for advices in cell culture protocols.

Supplementary material

11095_2016_2080_MOESM1_ESM.pdf (822 kb)
ESM 1 The online version of the article contains supplementary material, which includes a scheme summarizing the experimental methodology; a table with nanoparticles compositions; additional results from fluorescence microscopy imaging; SH-SY5Y cell fixation protocol optimized for STED microscopy; SH-SY5Y cell fixation protocol optimized for flow cytometry analysis; details of quantitative BDNF Rapid TM ELISA assay and methodology; and determination of curcumin encapsulation efficiency in nanocarriers. (PDF 821 kb)


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© Springer Science+Business Media New York 2016

Authors and Affiliations

  1. 1.Institut Galien Paris-Sud, CNRS UMR 8612, Univ. Paris-Sud, Université Paris-Saclay, LabEx LERMITChâtenay-Malabry cedexFrance
  2. 2.MIPSIT, Paris-Saclay Institute of Therapeutic Innovation (IPSIT-UMS3679 CNRS, US31 INSERM), Faculty of Pharmacy, Univ Paris Sud, Université Paris-SaclayChâtenay-MalabryFrance

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