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Sinapic Acid Protects SH-SY5Y Human Neuroblastoma Cells against 6-Hydroxydopamine-Induced Neurotoxicity.

ABSTRACT: Parkinson's disease (PD) is characterized by progressive dopaminergic neuron loss or dysfunction and is the second most prevalent neurodegenerative disorder after Alzheimer's disease. However, current therapeutic strategies for PD are limited to treating the outcomes of this disease rather than preventing it. Sinapic acid (SA) is a phenolic compound with potential antioxidant properties, which reportedly acts as a therapeutic agent against many diseases including cancer, as well as cardiac and liver diseases. However, little is known about the effects of SA against neurodegenerative disorders. Therefore, our study sought to evaluate the neuroprotective effects of non-cytotoxic concentrations of SA against 6-hydroxydopamine (6-OHDA)-induced neurotoxicity in SH-SY5Y human neuroblastoma cells, which we used as an in vitro PD model. SA increased cell viability and rescued the cells from 6-OHDA-induced apoptotic cell death. Additionally, oxidative stress responses were significantly blocked by SA, including reactive oxygen species (ROS) overproduction and decreased expression levels of antioxidant proteins. Notably, SA also attenuated mitochondrial dysfunction and endoplasmic reticulum (ER) stress. Moreover, SA dramatically inhibited the activation of mitogen-activated protein kinase (MAPK) proteins. Taken together, our findings highlight the potential PD prevention effects of SA, as well as its underlying mechanisms, making this compound a promising prevention and treatment agent for PD.

SUBMITTER: Tungalag T

PROVIDER: S-EPMC8000777 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundObesity-related central nervous system (CNS) pathologies like neuroinflammation and reactive gliosis are associated with high-fat diet (HFD) related elevation of saturated fatty acids like palmitic acid (PA) in neurons and astrocytes of the brain.MethodsHuman neuroblastoma cells SH-SY5Y (as a neuronal model) and human glioblastoma cells T98G (as an astrocytic model), were treated with 100-500 µM PA, oleic acid (OA) or lauric acid (LA) for 24 h or 48 h, and their cell viability was assessed by 3-(4,5-dimetylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. The effects of stable overexpression of γ-synuclein (γ-syn), a neuronal protein recently recognized as a novel regulator of lipid handling in adipocytes, and transient overexpression of Parkinson's disease (PD) α-synuclein [α-syn; wild-type (wt) and its pathogenic mutants A53T, A30P and E46K] in SH-SY5Y and T98G cells, were also evaluated. The effects of co-treatment of PA with paraquat (PQ), a Parkinsonian pesticide, and leptin, a hormone involved in the brain-adipose axis, were also assessed. Cell death mode and cell cycle were analyzed by Annexin V/PI flow cytometry. Reactive oxygen species (ROS) level was determined using 2',7'-dichlorofluorescien diacetate (DCFH-DA) assay and lipid peroxidation level was determined using thiobarbituric acid reactive substances (TBARS) assay.ResultsMTT assay revealed dose- and time-dependent PA cytotoxicity on SH-SY5Y and T98G cells, but not OA and LA. The cytotoxicity was significantly lower in SH-SY5Y-γ-syn cells, while transient overexpression of wt α-syn or its PD mutants (A30P and E46K, but not A53T) modestly (but still significantly) rescued the cytotoxicity of PA in SH-SY5Y and T98G cells. Co-treatment of increasing concentrations of PQ exacerbated PA's neurotoxicity. Pre-treatment of leptin, an anti-apoptotic adipokine, did not successfully rescue SH-SY5Y cells from PA-induced cytotoxicity-suggesting a mechanism of PA-induced leptin resistance. Annexin V/PI flow cytometry analysis revealed PA-induced increase in percentages of cells in annexin V-positive/PI-negative quadrant (early apoptosis) and subG0-G1 fraction, accompanied by a decrease in G2-M phase cells. The PA-induced ROS production and lipid peroxidation was at greater extent in T98G as compared to that in SH-SY5Y.DiscussionIn conclusion, PA induces apoptosis by increasing oxidative stress in neurons and astrocytes. Taken together, the results suggest that HFD may cause neuronal and astrocytic damage, which indirectly proposes that CNS pathologies involving neuroinflammation and reactive gliosis could be prevented via the diet regimen.

Project description:ObjectivesAstragaloside IV (AS-IV), the main active component of Astragalus membranaceus, bears anti-inflammatory, antioxidant, and neuroprotective activity. Parkinson's disease (PD) is a common neurodegenerative disease. This study explored the protective effect of AS-IV on the cell model of PD.Materials and methodsSH-SY5Y cells were incubated with different concentrations (10, 50, 100, 150, and 200 μM) of 6-hydroxydopamine (6-OHDA) for 0, 3, 6, 12, 24, and 48 h to establish the PD cell model. Different concentrations (0, 25, 50, 100, 150, and 200 μM) of AS-IV or 15 mM JAK2/STAT3 pathway inhibitor SC99 was added for intervention 2 h before 6-OHDA treatment. The viability and morphological damage of 6-OHDA-treated SH-SY5Y cells were measured using MTT assay and Hoechst 33258 staining. The expression of microtubule associated protein 2 (MAP2) was detected by immunofluorescence staining. The levels of inflammation and oxidative stress were measured using ELISA. Apoptosis of 6-OHDA-treated SH-SY5Y cells was detected using flow cytometry, and phosphorylation level of JAK2 and STAT3 were detected using Western blot analysis.ResultsThe survival rate of SH-SY5Y cells treated with 100 μM 6-OHDA for 24 h was about 50%. AS-IV (25-100 μM) significantly improved the viability (all p < 0.01), increased MAP2 expression, and repaired the morphological damage induced by 6-OHDA. AS-IV inhibited IL-1β, IL-6, and TNF-α level (all p < 0.05), reduced MDA and ROS content and increased SOD concentration, thereby reducing inflammation and oxidative stress (all p < 0.01) in 6-OHDA-treated SH-SY5Y cells. Moreover, AS-IV decreased apoptosis rate and Bax/Bcl-2 ratio induced by 6-OHDA (all p < 0.05). Mechanically, AS-IV significantly increased the phosphorylation of JAK2 and STAT3 (p < 0.01); the addition of SC99 decreased the cell viability, increased the apoptosis rate, enhanced the levels of inflammatory factors and oxidative stress.ConclusionAS-IV enhanced the cell viability, and inhibited apoptosis, inflammation and oxidative stress of 6-OHDA-treated SH-SY5Y cells via activating the JAK2/STAT3 signaling pathway. This study may confer novel insights for the management of PD.

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Sinapic Acid Protects SH-SY5Y Human Neuroblastoma Cells against 6-Hydroxydopamine-Induced Neurotoxicity.

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