Abstract
Over the past years, several lines of evidence have pointed out the efficacy of ferulic acid (FA) in counteracting oxidative stress elicited by β-amyloid or free radical initiators, based on the ability of this natural antioxidant to up-regulate the heme oxygenase-1 (HO-1) and biliverdin reductase (BVR) system. However, scarce results can be found in literature regarding the cytoprotective effects of FA in case of damage caused by neurotoxicants. The aim of this work is to investigate the mechanisms through which FA exerts neuroprotection in SH-SY5Y neuroblastoma cells exposed to the neurotoxin trimethyltin (TMT). FA (1–10 μM for 6 h) dose-dependently increased both basal and TMT (10 μM for 24 h)-induced HO-1 expression in SH-SY5Y cells by fostering the nuclear translocation of the transcriptional activator Nrf2. In particular, the co-treatment of FA (10 μM) with TMT was also responsible for the nuclear translocation of HO-1 in an attempt to further increase cell stress response in SH-SY5Y cells. In addition to HO-1, FA (1–10 μM for 6 h) dose-dependently increased the basal expression of BVR. The antioxidant and neuroprotective features of FA, through the increase of HO activity, were supported by the evidence that FA inhibited TMT (10 μM)-induced lipid peroxidation (evaluated by detecting 4-hydroxy-nonenal) and DNA fragmentation in SH-SY5Y cells and that this antioxidant effect was reversed by the HO inhibitor Zinc-protoporphyrin-IX (5 μM). Among the by-products of the HO/BVR system, carbon monoxide (CORM-2, 50 nM) and bilirubin (BR, 50 nM) significantly inhibited TMT-induced superoxide anion formation in SH-SY5Y cells. All together, these results corroborate the neuroprotective effect of FA through the up-regulation of the HO-1/BVR system, via carbon monoxide and BR formation, and provide the first evidence on the role of HO-1/Nrf2 axis in FA-related enhancement of cell stress response in human neurons.
Highlights
Since only one work has been found in literature concerning the effect of TMT on heme oxygenase-1 (HO-1), in a preliminary series of experiments, it was necessary to study the effect of TMT on the expression of heme oxygenase (HO)-1 and biliverdin reductase (BVR) in SH-SY5Y cells
Since one of the main mechanisms by which HO-1 is expressed is the translocation of the transcription factor Nrf2, from the cytoplasm to the nucleus, where it binds the antioxidant responsive element (ARE) region of the gene promoter HO-1, one of the goals of the study was to investigate whether the increased expression of HO-1, induced by ferulic acid (FA), had depended on the nuclear translocation of Nrf2 in SH-SY5Y cells
We investigated the neuroprotective effectiveness of the HO-1/BVR system -which plays a prominent role in the cellular stress response- on TMT neurotoxicity
Summary
For over 40 years, since Tenhunen et al (1969) demonstrated the heme-metabolizing activity of heme oxygenase (HO) with the formation of biliverdin (BV) and carbon monoxide (CO), and Mahin Maines – along with her group – documented the regulation and distribution of major isoforms of the protein, termed HO-1, and HO-2 (Cruse and Maines, 1988; Ewing and Maines, 1991, 1992; Maines, 1997), numerous studies have appeared in the literature showing the role of this enzyme in the modulation of biological functions, including the complex cellular response to stress in many cells and tissues (Mancuso et al, 2007; Motterlini and Foresti, 2014; Wegiel et al, 2014). A biological role for the HO/BVR system has been demonstrated in the central nervous system (CNS) where CO was involved in the processes of long-term potentiation (Verma et al, 1993; Zhuo et al, 1993) and neuropeptide release (Mancuso et al, 1997, 1999; Errico et al, 2010), whereas a strong antioxidant activity, through the interaction with ROS/RNS (Stocker et al, 1987; Barone et al, 2009b; Mancuso et al, 2012), and neurotrophic features (Mancuso et al, 2008) were documented for BR On these grounds, numerous researchers have put forth the hypothesis regarding the usefulness of HO1 and BVR up-regulation, in the case of diseases caused by an excessive production of free radicals, such as neurodegenerative disorders. A common approach is the use of natural products, such as (poly)phenols, abundant in fruits and vegetables, which have proved capable of increasing the expression of HO-1 in preclinical in vitro and in vivo systems (Scapagnini et al, 2011)
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