Abstract
Crocus sativus L. natural compounds have been extensively used in traditional medicine for thousands of years. Recent research evidence is now emerging in support of its therapeutic potential for different pathologies including neurodegenerative diseases. Herein, the C. sativus L. natural compounds trans-crocin 4 and trans-crocetin were selected for in depth molecular characterization of their potentially protective effects against Alzheimer’s Disease (AD), utilizing two AD neuronal cell culture models (SH-SY5Y overexpressing APP and PC12 expressing hyperphosphorylated tau). Biologically relevant concentrations, ranging from 0.1 μM to 1 mM, applied for 24 h or 72 h, were well tolerated by differentiated wild type SH-SY5Y and PC12 cells. When tested on neuronally differentiated SH-SY5Y-APP both trans-crocin 4 and trans-crocetin had significant effects against amyloidogenic pathways. Trans-crocin 4 significantly decreased of β-secretase, a key enzyme of the amyloidogenic pathway, and APP-C99, while it decreased γ-secretases that generate toxic beta-amyloid peptides. Similarly, trans-crocetin treatment led to a reduction in β- and γ-secretases, as well as to accumulation of cellular AβPP. When tested on the neuronally differentiated PC12-htau cells, both compounds proved effective in suppressing the active forms of GSK3β and ERK1/2 kinases, as well as significantly reducing total tau and tau phosphorylation. Collectively, our data demonstrate a potent effect of trans-crocin 4 and trans-crocetin in suppressing key molecular pathways of AD pathogenesis, rendering them a promising tool in the prevention and potentially the treatment of AD.
Highlights
Crocus sativus L., has been extensively used for over 3,000 years in Iran, India, China, Spain, Italy, and Greece for culinary, coloring, cosmetic and medicinal purposes
The initial step toward evaluating the molecular effects of trans-crocin 4 and trans-crocetin was the establishment of a suitable in vitro screening model. Toward this end the neuroblastoma, wild type SH-SY5Y and SH-SY5Y-APP cell lines were incubated with all-trans retinal for 6 days, while the pheochromocytoma wild type PC12 and PC12-htau cell lines were incubated with nerve growth factor (NGF) for 7 days, to enable differentiation to neuron-like cells
The successful differentiation was determined by a decrease in proliferation rates, the outgrowth of neurites (Supplementary Figure S3) (Cheung et al, 2009; Dwane et al, 2013), and the assessment of three neuronal markers, namely: (a) microtubule-associated protein 2 (MAP2), that stabilizes microtubules and is critical for neurite outgrowth and dendrite development (Goedert et al, 1991; Presgraves et al, 2004; Bond et al, 2012), (b) nuclear marker NeuN, a marker for post-mitotic neurons and maturation (Cheung et al, 2009; Agholme et al, 2010), and (c) neuron specific β-Tubulin III (TUJ-1), which is almost exclusively expressed in neurons and is a marker for differentiation and decreased proliferation (Figures 1, 2) (Constantinescu et al, 2007; Bell et al, 2013; Dwane et al, 2013)
Summary
Crocus sativus L. (saffron), has been extensively used for over 3,000 years in Iran, India, China, Spain, Italy, and Greece for culinary, coloring, cosmetic and medicinal purposes. Saffron has been shown to have anticonvulsant and antidepressant effects, with the latter being comparable to imipramine and fluoxetine in treating patients with mild to moderate depression (Akhondzadeh et al, 2004, 2005; Hosseinzadeh and Sadeghnia, 2005; Noorbala et al, 2005; Hosseinzadeh and Sadeghnia, 2007). It promotes cognitive functions in adult rodents previously exposed to amnestic agents (Zhang et al, 1994; Sugiura et al, 1995a; Zheng et al, 2007). Saffron inhibited TNFR-induced apoptosis of neuronally differentiated PC12 cells (Soeda et al, 2001), and protected neurons from the neurotoxic activity of 6-hydroxydopamine hydrobromide (Ahmad et al, 2005)
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