Abstract
The polyphenolic phytostilbene, trans-resveratrol, is found in high amounts in several types and tissues of plants, including grapes, and has been proposed to have beneficial effects in the central nervous system due to its activity as an antioxidant. The objective of the present study was to identify the mechanisms underlying the protective effects of resveratrol under conditions of oxidative stress or DNA damage, induced by the extracellularly applied oxidant, tert-butyl hydrogen peroxide, or UV-irradiation, respectively. In C6 glioma cells, a model system for glial cell biology and pharmacology, resveratrol was protective against both types of insult. Prevention of tau protein cleavage and of the formation of neurofibrillary tangles were identified as mechanisms of action of resveratrol-mediated protection in both paradigms of cellular damage. However, depending on the type of insult, resveratrol exerted its protective activity differentially: under conditions of chemically induced oxidative stress, inhibition of caspase activity, while with DNA damage, resveratrol regulated tau phosphorylation at Ser422. Results advance our understanding of resveratrol’s complex impact on cellular signaling pathway and contribute to the notion of resveratrol’s role as a pleiotropic therapeutic agent.
Highlights
Resveratrol (3,5,4 -trihydroxy-trans-stilbene) a polyphenol found in plant tissue, such as grapes, possesses antioxidant properties, which are being discussed as therapeutically relevant, e.g., in the context of resveratrol’s biological effects as a component of red wine [1,2]
We provide evidence that UV-irradiation of C6 cells leads to the activation of caspases, which in turn results in tau cleavage and neurofibrillary tangles (NFTs) formation, a process that can be blocked with the cell-permeable pan-caspase inhibitor N-Benzyloxycarbonyl-Val-Ala-Asp(O-Me) fluoromethyl ketone
We determined that tert-butyl hydroperoxide (tBHP) treatment induced caspase activation along with cleaved tau and NFT formation, as well. For both paradigms of oxidative stress and cell damage, UV-irradiation and tBHP treatment, we identified whether resveratrol was protective in the C6 cell line
Summary
Resveratrol (3,5,4 -trihydroxy-trans-stilbene) a polyphenol found in plant tissue, such as grapes, possesses antioxidant properties, which are being discussed as therapeutically relevant, e.g., in the context of resveratrol’s biological effects as a component of red wine [1,2]. We determined that tBHP treatment induced caspase activation along with cleaved tau and NFT formation, as well For both paradigms of oxidative stress and cell damage, UV-irradiation and tBHP treatment, we identified whether resveratrol was protective in the C6 cell line. PPrreettrreeaattmmeennttwwiitthhrreessvveerraattrroollaallssoopprreevveenntteeddttaauucclleeaavvaaggeeiinnUUVV--iirrrraaddiiaatteeddCC66 cceellllss ((FFiigguurree 22bb)) iinn spite of levels of caspase activity remaining elevated in UV-irradiated cells pretreated with resveratrol (Figure 2a). When C6 cells were pretreated with resveratrol prior to UV-irradiation, tau stress-mediated damage increased the levels of tau phosphorylation at Ser422 as compared to controls (Figure 4). Treatment of C6 cells with resveratrol prevented apoptosis induced by UV-irradiation and the resulting DNA damage or tBHP treatment and the concomitant oxidative stress (Figure 1). While the identification of such pleiotropic activity adds to the notion of resveratrol as a potentially therapeutically relevant compound, future studies might identify specific resveratrol binding partners responsible for the activation of protective mechanisms depending on the respective stimulus, inducing neurodegeneration
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