Neuroprotective effects of urolithin A on H₂O₂-induced oxidative stress-mediated apoptosis in SK-N-MC cells

Abstract

BACKGROUND/OBJECTIVES: Oxidative stress causes cell damage and death, which contribute to the pathogenesis of neurodegenerative diseases. Urolithin A (UA), a gut microbial-derived metabolite of ellagitannins and ellagic acid, has high bioavailability and various health benefits such as antioxidant and anti-inflammatory effects. However, it is unknown whether it has protective effects against oxidative stress-induced cell death. We investigated whether UA ameliorates H2O2-induced neuronal cell death. MATERIALS/METHODS: We induced oxidative damage with 300 μM H2O2 after UA pretreatment at concentrations of 1.25, 2.5, and 5 μM in SK-N-MC cells. Cytotoxicity and cell viability were determined using the CCK-8 assay. The formation of reactive oxygen species (ROS) was measured using a 2,7-dichlorofluorescein diacetate assay. Hoechst 33342 staining was used to characterize morphological changes in apoptotic cells. The expressions of apoptosis proteins were measured using Western blotting. RESULTS: UA significantly increased cell viability and decreased intracellular ROS production in a dose-dependent manner in SK-N-MC cells. It also decreased the Bax/Bcl-2 ratio and the expressions of cytochrome c, cleaved caspase-9, cleaved caspase-3, and cleaved PARP. In addition, it suppressed the phosphorylation of the p38 mitogen-activated protein kinase (MAPK) pathway. CONCLUSIONS: UA attenuates oxidative stress-induced apoptosis via inhibiting the mitochondrial-related apoptosis pathway and modulating the p38 MAPK pathway, suggesting that it may be an effective neuroprotective agent.

Effects of Urolithin A on Mitochondrial Parameters in a Cellular Model of Early Alzheimer Disease

“…In general, the observed increases in OXPHOS-related gene expression could indicate a delayed response of the cells towards UA’s effect on them. Therefore, based on our data of SY5Y cells, we are unable to confirm UA’s effect as an antioxidant, which has been reported elsewhere [ 33 , 50 , 51 ], but instead the results could point towards a hormetic response of the cell towards UA exposure.…”

An Integrated Analysis of Network Pharmacology and Experimental Validation to Reveal the Mechanism of Chinese Medicine Formula Naotaifang in Treating Cerebral Ischemia-Reperfusion Injury

“…Bcl-2 can promote cell survival, while Bax facilitates apoptosis. 88 In the present study, our data exhibited that NTF decreased the number of apoptotic neuronal cells, raised the expression of Bcl-2 and reduced the expression of Bax, which signified that NTF has an anti-apoptotic effect in CIRI. Taken together, the STAT3/PI3K/AKT signaling pathway may be a critical therapeutic target for reducing apoptosis and enhancing neurogenesis in the treatment of NTF in ischemia stroke and CIRI.…”

Ellagic Acid-Derived Urolithins as Modulators of Oxidative Stress

“…Both urolithins showed protective effects with an increase in cellular viability after induction of oxidative stress with 2,3-dimethoxy-1,4-naphthoquinone (DMNQ) [56]. Kim [57]. Both of these studies were conducted in human neuroblastoma SK-N-MC cells, as reported by the authors.…”

“…Here, after treatment with urolithin A, the expressions of cytochrome c, cleaved caspase-9, cleaved caspase-3, and cleaved poly (ADP-ribose) polymerase (PARP) were suppressed, confirming that urolithin A attenuated apoptotic cell death in H 2 O 2 -exposed SK-N-MC cells. In brief, urolithin A decreased ROS production in cells, inhibited the mitochondrial-related apoptosis pathway, and modulated the p-38 MAPK pathway [ 57 ].…”