Nutraceuticals to promote neuronal plasticity in response to corticosterone-induced stress in human neuroblastoma cells

Abstract

Objectives: To search for novel compounds that will protect neuronal cells under stressed conditions that may help to restore neuronal plasticity.

Methods: A model of corticosterone (CORT)-induced stress in human neuroblastoma cells (SH-SY5Y) was used to compare the efficacy of 6 crude extracts and 10 pure compounds (6 polyphenols, 2 carotenoids, 1 amino acid analogue, and 1 known antidepressant drug) to increase neuronal plasticity and to decrease cytotoxicity.

Results: Astaxanthin (among pure compounds) and phlorotannin extract of Fucus vesiculosus (among crude extracts) showed a maximum increase in cell viability in the presence of excess CORT. BDNF-VI mRNA expression in SH-SY5Y cells was significantly improved by pretreatment with quercetine, astaxanthin, curcumin, fisetin, and resveratrol. Among crude extracts, xanthohumol, phlorotannin extract (Ecklonia cava), petroleum ether extract (Nannochloropsis oculata), and phlorotannin extract (F. vesiculosus) showed a significant increase in BDNF-VI mRNA expression. CREB1 mRNA expression was significantly improved by astaxanthin, β-carotene, curcumin, and fluoxetine whereas none of the crude extracts caused significant improvement. As an adjunct of fluoxetine, phlorotannin extract (F. vesiculosus), β-carotene, and xanthohumol have resulted in significant improvement in BDNF-VI mRNA expression and CREB1 mRNA expression was significantly improved by phlorotannin extract (F. vesiculosus). Significant improvement in mature BDNF protein expression by phlorotannin extract (F. vesiculosus) and β-carotene as an adjunct of fluoxetine confirm their potential to promote neuronal plasticity against CORT-induced stress.

Discussion: The carotenoids, flavonoids, namely quercetine, curcumin, and low molecular weight phlorotannin-enriched extract of F. vesiculosus may serve as potential neuroprotective agents promoting neuronal plasticity in vitro.

Graphical abstract: Cascade of events associated with disturbed homeostatic balance of glucocorticoids and impact of phlorotannin extract (F. vesiculosus) and β-carotene in restoring neuronal plasticity. Abbreviation: TrKB, tropomyosin receptor kinase B; P-ERK, phosphorylated extracellular signal-related kinase; PI3K, phosphatidylinositol 3-kinase; Akt, protein kinase B; Ca++/CaMK, calcium/calmodulin-dependent protein kinase; pCREB, phosphorylated cAMP response element-binding protein; CRE, cAMP response elements, CORT, corticosterone; and BDNF; brain-derived neurotrophic factor.

GRAPHICAL ABSTRACT

Keywords:

• SH-SY5Y cells
• CORT
• Phlorotannin
• BDNF
• CREB
• Nutraceuticals
• EPA

ORCID

Snehal Gite http://orcid.org/0000-0002-8091-160X

R. Paul Ross http://orcid.org/0000-0003-4876-8839

Dara Kirke http://orcid.org/0000-0003-3102-7946

Dagmar B. Stengel http://orcid.org/0000-0001-5871-9550

Timothy G. Dinan http://orcid.org/0000-0002-2316-7220

John F. Cryan http://orcid.org/0000-0001-5887-2723

Catherine Stanton http://orcid.org/0000-0002-6724-7011

Additional information

Funding

This project (Grant-Aid Agreement No. MFFRI/07/01) was carried out under the Sea Change Strategy, NutraMara programme and SMART FOOD: ‘Science Based “Intelligent”/Functional and Medical Foods for Optimum Brain Health, Targeting Depression and Cognition’ project (Ref No. 13/F/411) with the support of the Marine Institute and the Department of Agriculture, Food and the Marine (DAFM) in Ireland and in part by the Science Foundation Ireland (SFI)-funded APC Microbiome Institute, as well as Teagasc Walsh Fellowship number 2013027 (DK).