Abstract
The interest in the biological properties of grapevine polyphenols (PPs) in neuroprotection is continuously growing in the hope of finding translational applications. However, there are several concerns about the specificity of action of these molecules that appear to act non-specifically on the permeability of cellular membranes. Naturally occurring neuronal death (NOND) during cerebellar maturation is a well characterized postnatal event that is very useful to investigate the death and rescue of neurons. We here aimed to establish a baseline comparative study of the potential to counteract NOND of certain grapevine PPs of interest for the oenology. To do so, we tested ex vivo the neuroprotective activity of peonidin- and malvidin-3-O-glucosides, resveratrol, polydatin, quercetin-3-O-glucoside, (+)-taxifolin, and (+)-catechin. The addition of these molecules (50 μM) to organotypic cultures of mouse cerebellum explanted at postnatal day 7, when NOND reaches a physiological peak, resulted in statistically significant (two-tailed Mann–Whitney test—p < 0.001) reductions of the density of dead cells (propidium iodide+ cells/mm2) except for malvidin-3-O-glucoside. The stilbenes were less effective in reducing cell death (to 51–60%) in comparison to flavanols, (+)-taxifolin and quercetin 3-O-glucoside (to 69–72%). Thus, molecules with a -OH group in ortho position (taxifolin, quercetin 3-O-glucoside, (+)-catechin, and peonidin 3-O-glucoside) have a higher capability to limit death of cerebellar neurons. As NOND is apoptotic, we speculate that PPs act by inhibiting executioner caspase 3.
Highlights
We know a great deal about the chemistry of grapevine polyphenols (PPs) because they are widely studied for their implications in wine production and biological role in the grapevine response to biotic and abiotic stress
We here tested peonidin 3-O-glucoside (Pn-3OG) as the main representative of the anthocyanins in a few but locally very important varieties of Vitis vinifera [30] and malvidin 3-O-glucoside (Mv-3OG), quantitatively, without any doubt, the most important anthocyanin found in grape berries, musts and wines [31]. Another reason why we investigated the neuroprotective effect of Mv-3OG is that in vitro studies on SH-SY5Y human neuroblastoma cells [32] or C6 glial cells [29] have demonstrated protection against oxidative stress
As PPs are soluble in ethanolic solutions and ethanol itself induces death in neurons, we have devised a series of experiments in which cerebellar slices were maintained in vitro in the presence of progressively increasing concentrations of ethanol to assess the outcome on cerebellar neuronal death (NOND) (Figure 1)
Summary
We know a great deal about the chemistry of grapevine polyphenols (PPs) because they are widely studied for their implications in wine production and biological role in the grapevine response to biotic and abiotic stress. There is a huge body of preclinical evidence on the numerous cellular mechanisms targeted by these substances (resveratrol, in particular) in relation to several pathological conditions including neurological diseases [1,2], but results are often heterogeneous or inconsistent. There may be several reasons for the heterogeneity and lack of consistency of in vitro and/or animal studies on (grapevine) PPs. There may be several reasons for the heterogeneity and lack of consistency of in vitro and/or animal studies on (grapevine) PPs These studies have come under heavy criticism because they have used artificially high doses.
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