Mechanisms and Neuroprotective Activities of Stigmasterol Against Oxidative Stress-Induced Neuronal Cell Death via Sirtuin Family

Abstract

Background: Accumulating studies have confirmed that oxidative stress leads to the death of neuronal cells and is associated with the progression of neurodegenerative diseases, including Alzheimer's disease (AD). Despite the compelling evidence, there is a drawback to the use of the antioxidant approach for AD treatment, partly due to limited blood-brain barrier (BBB) permeability. Phytosterol is known to exhibit BBB penetration and exerts various bioactivities such as antioxidant and anticancer effects, and displays a potential treatment for dyslipidemia, cardiovascular disease, and dementia.Objective: In this study, the protective effects of stigmasterol, a phytosterol compound, on cell death induced by hydrogen peroxide (H2O2) were examined in vitro using human neuronal cells (SH-SY5Y cells).Methods: MTT assay, reactive oxygen species measurement, mitochondrial membrane potential assay, apoptotic cell measurement, and protein expression profiles were performed to determine the neuroprotective properties of stigmasterol.Results: H2O2 exposure significantly increased the levels of reactive oxygen species (ROS) within the cells thereby inducing apoptosis. On the contrary, pretreatment with stigmasterol maintained ROS levels inside the cells and prevented oxidative stress-induced cell death. It was found that pre-incubation with stigmasterol also facilitated the upregulation of forkhead box O (FoxO) 3a, catalase, and anti-apoptotic protein B-cell lymphoma 2 (Bcl-2) in the neurons. In addition, the expression levels of sirtuin 1 (SIRT1) were also increased while acetylated lysine levels were decreased, indicating that SIRT1 activity was stimulated by stigmasterol, and the result was comparable with the known SIRT1 activator, resveratrol.Conclusion: Taken together, these results suggest that stigmasterol could be potentially useful to alleviate neurodegeneration induced by oxidative stress.

The Genus Alternanthera: Phytochemical and Ethnopharmacological Perspectives

“…They had noticed various mechanisms behind it like inhibition of lipid peroxidation in the whole brain, downregulation of neuroinflammatory cytokines (IL-1β, IL-6, and TNF-α), etc ( Khamphukdee et al, 2021 ). Phytomolecules like Luteolin and luteolin analogs ( Delgado et al, 2021 ), Vitexin ( Malar et al, 2020 ; Zhang et al, 2021 ), Quercetin ( Yao et al, 2010 ), Torosaflavone E ( Khamphukdee et al, 2021 ), Demethyl torosaflavone D ( Khamphukdee et al, 2021 ), β-Sitosterol ( Kim et al, 2008 ), Stigmasterol ( Park S. J. et al, 2012 ; Pratiwi et al, 2021 ), Ursolic acid ( Habtemariam, 2019 ), Oleanolic acid and oleanolic acid analogs ( Lin et al, 2021 ), Caffeic acid ( Khan et al, 2013 ; Deshmukh et al, 2016 ), Quinic acid ( Liu et al, 2020 ), p-Coumaric acid ( Kim H.-B. et al, 2017 ), β-Carboline ( Zhao et al, 2013 ; Li et al, 2018 ), Malic acid ( Tian et al, 2021 ), Blumenol A ( Emir et al, 2019 ), Phytol ( Sathya et al, 2020 ), and Pheophytin A ( Park et al, 2014 ) which were earlier reported from Alternanthera philoxeroides (Mart.)…”

Phytosterols: Potential Metabolic Modulators in Neurodegenerative Diseases

“…According to the binding analysis, SIRT1 interacted with stigmasterol and resveratrol; both compounds bind to Thr 209 and Pro 212 by van der Waals and hydrophobic interactions, respectively. Moreover, they also shared binding interactions with Phe 414 , Asp 292 , Gln 294 , and Ala 295 [62]. Stigmasterol was also reported to inhibit several pro-inflammatory cytokines in IL-1β-treated cells without affecting IL-6 levels, suggesting its role in the IL-1β-induced NF-κB inflammatory pathway [66].…”

“…Stigmasterol displayed neuroprotective activity against glutamate-induced toxicity by inhibition of reactive oxygen species (ROS) and Ca 2+ production in in vitro studies [61]. To investigate the possible neuroprotective mechanisms of stigmasterol, an H 2 O 2 -induced oxidative stress model in SH-SY5Y neuroblastoma cells was established [62]. H 2 O 2 exposure raised the levels of ROS significantly within the cells, inducing apoptosis.…”

“…It also upregulated catalase, forkhead box O (FoxO) 3a, and anti-apoptotic protein B-cell lymphoma 2 (Bcl-2) in the neurons. Additionally, it also increased the expression levels of sirtuin 1 (SIRT1) and decreased the levels of acetylated lysine [62]. Sirtuins are highly conserved NAD (+)-dependent enzymes that have positive effects in age-related neurodegenerative diseases.…”

Mitochondrial Sirtuins in Chronic Degenerative Diseases: New Metabolic Targets in Colorectal Cancer

“…This property achieves SIRT3 as a relevant target of interest for the comprehension of neurodegeneration and inspiration for new target therapies [ 52 ]. A recent study described the stigmasterol treatment in the prevention of neurodegeneration mechanisms, elucidating the neuroprotective role of SIRT1 against hydrogen-peroxide-induced toxicity [ 53 ]. In vitro studies on human neuronal cells showed that stigmasterol activates SIRT1 which, in turn, deacetylates and activates catalases, thus promoting the production of antioxidants and the resistance against oxidative stress [ 53 ].…”