Protective Effect of NGR1 against Glutamate-Induced Cytotoxicity in HT22 Hippocampal Neuronal Cells by Upregulating the SIRT1/Wnt/β-Catenin Pathway

Notoginsenoside R1 (NGR1) is an active compound isolated from Panax notoginseng. Despite the NGR1 having been used as a traditional medicine, little is known about the neuroprotective effects. In this study, we investigate the protective effects of NGR1 against glutamate-induced cytotoxicity in HT22 cells and its possible molecular mechanism. We assessed the toxicity of NGR1 and the protective activity by MTT assay. The levels of oxidative stress indices superoxide dismutase (SOD), glutathione (GSH), and mitochondrial membrane potential (MMP) were measured by the kits. The levels of reactive oxygen species (ROS) and Ca2+ concentration were measured by flow cytometry. Furthermore, we determined the expression of mitochondrial dysfunction related protein PINK1, Parkin, silent mating type information regulation 2 homolog-1 (sirtuin 1; SIRT1), and Wnt/β-catenin by Western blotting. Here, we discovered that glutamate treatment led to cell viability loss, apoptosis facilitation, Ca2+ upregulation, MMP fluorescence intensity downregulation, and ROS generation of HT22 cells. In parallel, expression of Parkin was declined by glutamate. While, NGR1 treatment alleviated all the above phenomena. We further clarified that NGR1 alleviated glutamate-induced oxidative stress, apoptosis, and mitochondrial dysfunction by upregulating SIRT1 to activate Wnt/β-catenin pathways. These findings demonstrate that NGR1 alleviated glutamate-induced cell damage, and NGR1 may play a protective role in neurological complications.

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FAM3A Protects HT22 Cells Against Hydrogen Peroxide-Induced Oxidative Stress Through Activation of PI3K/Akt but not MEK/ERK Pathway

Cellular Physiology and Biochemistry ◽

10.1159/000438512 ◽

2015 ◽

Vol 37 (4) ◽

pp. 1431-1441 ◽

Cited By ~ 20

Author(s):

Qing Song ◽

Wen-Li Gou ◽

Rong Zhang

Keyword(s):

Oxidative Stress ◽

Hydrogen Peroxide ◽

Lipid Peroxidation ◽

Cell Viability ◽

Cell Damage ◽

Ros Generation ◽

Erk Pathway ◽

Protective Effects ◽

Ht22 Cells ◽

Ldh Release

Background/Aims: Oxidative stress-induced cell damage is involved in many neurological diseases. FAM3A is the first member of family with sequence similarity 3 (FAM3) gene family and its biological function remains largely unknown. Methods: This study aimed to determine its role in hydrogen peroxide (H2O2) induced injury in neuronal HT22 cells. The protective effects were measured by cell viability, lactate dehydrogenase (LDH) release and apoptosis, and oxidative stress was assayed by reactive oxygen species (ROS) generation, ATP synthesis and lipid peroxidation. By using selective inhibitors, the involvement of PI3K/Akt and MEK/ERK pathways were also investigated. Results: The results of fluorescence staining revealed that H2O2 significantly decreased the expression of FAM3A protein, which was shown to be subcellularly located in mitochondria. Up-regulation of FAM3A by lentivirus transfection markedly increased cell viability and decreased LDH release after H2O2 treatment. The anti-apoptotic activity of FAM3A was demonstrated by the reduced mitochondrial cytochrome c release, decreased activation of caspase-3 and the results of flow cytometry. Overexpression of FAM3A attenuated intracellular ROS generation and loss of ATP production induced by H2O2, and subsequently inhibited lipid peroxidation. In addition, overexpression of FAM3A significantly increased the activation of Akt and ERK in H2O2 injured HT22 cells. By using Akt and ERK specific inhibitors, we found that inhibition of PI3K/Akt, but not MEK/ERK pathway, partially prevented FAM3A-induced protection against H2O2. Conclusion: These results suggest that FAM3A has protective effects against H2O2-induced oxidative stress by reducing ROS accumulation and apoptosis, and these protective effects are dependent on the activation of PI3K/Akt pathway.

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Ethanol Extract of Maclura tricuspidata Fruit Protects SH-SY5Y Neuroblastoma Cells against H2O2-Induced Oxidative Damage via Inhibiting MAPK and NF-κB Signaling

International Journal of Molecular Sciences ◽

10.3390/ijms22136946 ◽

2021 ◽

Vol 22 (13) ◽

pp. 6946

Author(s):

Weishun Tian ◽

Suyoung Heo ◽

Dae-Woon Kim ◽

In-Shik Kim ◽

Dongchoon Ahn ◽

...

Keyword(s):

Oxidative Stress ◽

Free Radical ◽

Oxidative Damage ◽

Cell Damage ◽

Antioxidant Properties ◽

Radical Scavenging ◽

Biologically Active ◽

Mitogen Activated Protein Kinase ◽

Protective Effects ◽

Neuroprotective Effects

Free radical generation and oxidative stress push forward an immense influence on the pathogenesis of neurodegenerative diseases such as Alzheimer’s disease and Parkinson’s disease. Maclura tricuspidata fruit (MT) contains many biologically active substances, including compounds with antioxidant properties. The current study aimed to investigate the neuroprotective effects of MT fruit on hydrogen peroxide (H2O2)-induced neurotoxicity in SH-SY5Y cells. SH-SY5Y cells were pretreated with MT, and cell damage was induced by H2O2. First, the chemical composition and free radical scavenging properties of MT were analyzed. MT attenuated oxidative stress-induced damage in cells based on the assessment of cell viability. The H2O2-induced toxicity caused by ROS production and lactate dehydrogenase (LDH) release was ameliorated by MT pretreatment. MT also promoted an increase in the expression of genes encoding the antioxidant enzymes superoxide dismutase (SOD) and catalase (CAT). MT pretreatment was associated with an increase in the expression of neuronal genes downregulated by H2O2. Mechanistically, MT dramatically suppressed H2O2-induced Bcl-2 downregulation, Bax upregulation, apoptotic factor caspase-3 activation, Mitogen-activated protein kinase (MAPK) (JNK, ERK, and p38), and Nuclear factor-κB (NF-κB) activation, thereby preventing H2O2-induced neurotoxicity. These results indicate that MT has protective effects against H2O2-induced oxidative damage in SH-SY5Y cells and can be used to prevent and protect against neurodegeneration.

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Allicin Protects PC12 Cells Against 6-OHDA-Induced Oxidative Stress and Mitochondrial Dysfunction via Regulating Mitochondrial Dynamics

Cellular Physiology and Biochemistry ◽

10.1159/000430271 ◽

2015 ◽

Vol 36 (3) ◽

pp. 966-979 ◽

Cited By ~ 44

Author(s):

Hao Liu ◽

Ping Mao ◽

Jia Wang ◽

Tuo Wang ◽

Chang-Hou Xie

Keyword(s):

Oxidative Stress ◽

Mitochondrial Dysfunction ◽

Pc12 Cells ◽

Atp Synthesis ◽

Ros Generation ◽

Antioxidant Enzyme Activities ◽

Protective Effects ◽

Cytochrome C Release ◽

Endogenous Antioxidant

Background: Parkinson disease (PD) is a common adult-onset neurodegenerative disorder, and PD related neuronal injury is associated with oxidative stress and mitochondrial dysfunction. Allicin, the main biologically active compound derived from garlic, has been shown to exert various anti-oxidative and anti-apoptotic activities in in vitro and in vivo studies. Methods: The present study aimed to investigate the potential protective role of allicin in an in vitro PD model induced by 6-hydroxydopamine (6-OHDA) in PC12 cells. The protective effects were measured by cell viability, decreased lactate dehydrogenase (LDH) release and flow cytometry, and the anti-oxidative activity was determined by reactive oxygen species (ROS) generation, lipid peroxidation and the endogenous antioxidant enzyme activities. Mitochondrial function in PC12 cells was detected by mitochondrial membrane potential (MMP) collapse, cytochrome c release, mitochondrial ATP synthesis, and the mitochondrial Ca2+ buffering capacity. To investigate the potential mechanism, we also measured the expression of mitochondrial biogenesis factors, mitochondrial morphological dynamic changes, as well as detected mitochondrial dynamic proteins by western blot. Results: We found that allicin treatment significant increased cell viability, and decreased LDH release and apoptotic cell death after 6-OHDA exposure. Allicin also inhibited ROS generation, reduced lipid peroxidation and preserved the endogenous antioxidant enzyme activities. These protective effects were associated with suppressed mitochondrial dysfunction, as evidenced by decreased MMP collapse and cytochrome c release, preserved mitochondrial ATP synthesis, and the promotion of mitochondrial Ca2+ buffering capacity. In addition, allicin significantly enhanced mitochondrial biogenesis and prevented fragmentation of mitochondrial network after 6-OHDA treatment. The results of western blot analysis showed that the 6-OHDA induced decrease in the expression of optic atrophy type 1 (Opa-1), increase in mitochondrial fission 1 (Fis-1) and dynamin-related protein 1 (Drp-1) were all partially revised by allicin. Conclusion: In summary, our data strongly suggested that allicin treatment can exert protective effects against PD related neuronal injury through inhibiting oxidative stress and mitochondrial dysfunction with dynamic changes.

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Daphnetin Attenuated Cisplatin-Induced Acute Nephrotoxicity With Enhancing Antitumor Activity of Cisplatin by Upregulating SIRT1/SIRT6-Nrf2 Pathway

Frontiers in Pharmacology ◽

10.3389/fphar.2020.579178 ◽

2020 ◽

Vol 11 ◽

Author(s):

Xiaoye Fan ◽

Wei Wei ◽

Jingbo Huang ◽

Liping Peng ◽

Xinxin Ci

Keyword(s):

Oxidative Stress ◽

Mitochondrial Dysfunction ◽

Cell Damage ◽

Protective Effects ◽

Normal Tissues ◽

Nrf2 Signaling Pathway ◽

Apoptosis Pathways ◽

Underlying Mechanisms

Cisplatin (CDDP) is a widely used drug for cancer treatment that exhibits major side effects in normal tissues, such as nephrotoxicity in kidneys. The Nrf2 signaling pathway, a regulator of mitochondrial dysfunction, oxidative stress and inflammation, is a potential therapeutic target in CDDP-induced nephrotoxicity. We explored the underlying mechanisms in wild-type (WT) and Nrf2−/− mice on CDDP-induced renal dysfunction in vivo. We found that Nrf2 deficiency aggravated CDDP-induced nephrotoxicity, and Daph treatment significantly ameliorated the renal injury characterized by biochemical markers in WT mice and reduced the CDDP-induced cell damage. In terms of the mechanism, Daph upregulated the SIRT1 and SIRT6 expression in vivo and in vitro. Furthermore, Daph inhibited the expression level of NOX4, whereas it activated Nrf2 translocation and antioxidant enzymes HO-1 and NQO1, and alleviated oxidative stress and mitochondrial dysfunction. Moreover, Daph suppressed CDDP-induced NF-κB and MAPK inflammation pathways, as well as p53 and cleaved caspase-3 apoptosis pathways. Notably, the protective effects of Daph in WT mice were completely abrogated in Nrf2−/− mice. Moreover, Daph enhanced, rather than attenuated, the tumoricidal effect of CDDP.

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Neuroprotective Effects of Glochidion zeylanicum Leaf Extract against H2O2/Glutamate-Induced Toxicity in Cultured Neuronal Cells and Aβ-Induced Toxicity in Caenorhabditis elegans

Biology ◽

10.3390/biology10080800 ◽

2021 ◽

Vol 10 (8) ◽

pp. 800

Author(s):

Chatrawee Duangjan ◽

Panthakarn Rangsinth ◽

Shaoxiong Zhang ◽

Xiaojie Gu ◽

Michael Wink ◽

...

Keyword(s):

Oxidative Stress ◽

Caenorhabditis Elegans ◽

Leaf Extract ◽

Neuronal Cells ◽

Antioxidant Properties ◽

Ros Generation ◽

Protective Effects ◽

Neuroprotective Effects ◽

Antioxidant Genes ◽

Age Related

Oxidative stress plays a crucial role in the development of age-related neurodegenerative diseases. Previously, Glochidion zeylanicum methanol (GZM) extract has been reported to have antioxidant and anti-aging properties. However, the effect of GZM on neuroprotection has not been reported yet; furthermore, the mechanism involved in its antioxidant properties remains unresolved. The study is aimed to demonstrate the neuroprotective properties of GZM extract and their underlying mechanisms in cultured neuronal (HT-22 and Neuro-2a) cells and Caenorhabditis elegans models. GZM extract exhibited protective effects against glutamate/H2O2-induced toxicity in cultured neuronal cells by suppressing the intracellular reactive oxygen species (ROS) generation and enhancing the expression of endogenous antioxidant enzymes (SODs, GPx, and GSTs). GZM extract also triggered the expression of SIRT1/Nrf2 proteins and mRNA transcription of antioxidant genes (NQO1, GCLM, and EAAT3) which are the master regulators of cellular defense against oxidative stress. Additionally, GZM extract exhibited protective effects to counteract β-amyloid (Aβ)-induced toxicity in C. elegans and promoted neuritogenesis properties in Neuro-2a cells. Our observations suggest that GZM leaf extract has interesting neuritogenesis and neuroprotective potential and can possibly act as potential contender for the treatment of oxidative stress-induced Alzheimer’s disease (AD) and related neurodegenerative conditions; however, this needs to be studied further in other in vivo systems.

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Oxidative Stress, Mitochondrial Dysfunction, and Neuroprotection of Polyphenols with Respect to Resveratrol in Parkinson’s Disease

Biomedicines ◽

10.3390/biomedicines9080918 ◽

2021 ◽

Vol 9 (8) ◽

pp. 918

Author(s):

Heng-Chung Kung ◽

Kai-Jung Lin ◽

Chia-Te Kung ◽

Tsu-Kung Lin

Keyword(s):

Oxidative Stress ◽

Parkinson’S Disease ◽

Parkinson's Disease ◽

Mitochondrial Dysfunction ◽

Mitochondrial Dynamics ◽

Critical Role ◽

Neuronal Loss ◽

Ros Generation ◽

Neuroprotective Effects ◽

Dopaminergic Neuronal Loss

Parkinson’s disease (PD) is the second most common neurodegenerative disease and is characterized by dopaminergic neuronal loss. The exact pathogenesis of PD is complex and not yet completely understood, but research has established the critical role mitochondrial dysfunction plays in the development of PD. As the main producer of cytosolic reactive oxygen species (ROS), mitochondria are particularly susceptible to oxidative stress once an imbalance between ROS generation and the organelle’s antioxidative system occurs. An overabundance of ROS in the mitochondria can lead to mitochondrial dysfunction and further vicious cycles. Once enough damage accumulates, the cell may undergo mitochondria-dependent apoptosis or necrosis, resulting in the neuronal loss of PD. Polyphenols are a group of natural compounds that have been shown to offer protection against various diseases, including PD. Among these, the plant-derived polyphenol, resveratrol, exhibits neuroprotective effects through its antioxidative capabilities and provides mitochondria protection. Resveratrol also modulates crucial genes involved in antioxidative enzymes regulation, mitochondrial dynamics, and cellular survival. Additionally, resveratrol offers neuroprotective effects by upregulating mitophagy through multiple pathways, including SIRT-1 and AMPK/ERK pathways. This compound may provide potential neuroprotective effects, and more clinical research is needed to establish the efficacy of resveratrol in clinical settings.

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Epigallocatechin Gallate Protects against TNFα- or H2O2- Induced Apoptosis by Modulating Iron Related Proteins in a Cell Culture Model

International Journal for Vitamin and Nutrition Research ◽

10.1024/0300-9831/a000493 ◽

2018 ◽

Vol 88 (3-4) ◽

pp. 158-165 ◽

Cited By ~ 5

Author(s):

Qi Xu ◽

Anumantha G. Kanthasamy ◽

Manju B. Reddy

Keyword(s):

Oxidative Stress ◽

Cell Viability ◽

Caspase 3 ◽

Epigallocatechin Gallate ◽

Ros Generation ◽

Dependent Manner ◽

Protective Effects ◽

Neuroprotective Effects ◽

Cell Viability Assay ◽

Hepcidin Expression

Abstract. Oxidative stress, iron dysregulation, and inflammation have been implicated in the pathogenesis of Parkinson’s disease (PD). Considering the entwined relationship among these factors, epigallocatechin gallate (EGCG) may be a good candidate for PD treatment due to its protective effects against those factors. The objective of this study is to determine whether EGCG protects N27 dopaminergic neuronal cells from H2O2 - and TNFα- induced neurotoxicity. Seven treatments were included: control, H2O2, TNFα, FeSO4, H2O2 + EGCG, TNFα + EGCG, FeSO4 + EGCG. Cells were pretreated with 10 μM EGCG, followed by 50 μM H2O2, 30 ng/ml TNFα or 50 μM FeSO4. Neuroprotective effects of EGCG were assessed by cell viability assay, caspase-3 activity, intracellular reactive oxygen species (ROS) generation, and iron related protein expressions. Caspase-3 activity was increased to 2.8 fold (P < 0.001) and 1.5 fold (P < 0.01) with H2O2 and TNFα treatment; However, EGCG pretreatment significantly decreased the caspase activity by 50.2% (P < 0.001) and 30.1% (P < 0.05). Similarly, cell viability was reduced to 69.2% (P < 0.01) and 89% (P < 0.01) by H2O2 and TNFα, which was partially blocked by EGCG pretreatment. Also, EGCG significantly (P < 0.001) protected against H2O2- induced ROS in a time dependent manner. In addition, both H2O2 and TNFα significantly (P < 0.05) upregulated hepcidin expression and marginally reduced ferroportin (Fpn) expression unlike iron treatment alone. Collectively, our results show that EGCG protects against both TNFα- and H2O2- induced neuronal apoptosis. The observed neuroprotection may be through the inhibition of oxidative stress and inflammation which is possibly mediated mainly by hepcidin and partially by Fpn.

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Neuroprotective Effects of Extracts from the Radix Curcuma aromatica on H2O2-induced Damage in PC12 Cells

Combinatorial Chemistry & High Throughput Screening ◽

10.2174/1386207321666181005121457 ◽

2018 ◽

Vol 21 (8) ◽

pp. 571-582 ◽

Cited By ~ 1

Author(s):

Juxiang Liu ◽

Lianli Zhang ◽

Dan Liu ◽

Baocai Li ◽

Mi Zhang

Keyword(s):

Oxidative Stress ◽

Pc12 Cells ◽

Caspase 3 ◽

Cell Damage ◽

Positive Control ◽

Neuroprotective Activity ◽

Antioxidant Enzyme Activities ◽

Morphologic Change ◽

Neuroprotective Effects ◽

Etoh Extract

Aim & Objectives: Curcuminoids are characteristic constituents in Curcuma, displaying obviously neuroprotective activities against oxidative stress. As one of the Traditional Chinese Medicines from Curcuma, the radix of Curcuma aromatica is also rich in those chemicals, but its neuroprotective activity and mechanism remain unknown. The aim of the current study is to evaluate the neuroprotective effects of extracts from the radix of C. aromatica (ECAs) on H2O2-damaged PC12 cells. Material and Methods: The model of oxidative stress damage was established by treatment of 400 µM H2O2 on PC12 to induce cell damage. After the treatment of ECWs for 24 h, the cell viability, LDH, SOD, CAT and GSH were measured to evaluate the neuroprotection of ECAs on that model. The potential action mechanism was studied by measurement of level of ROS, cell apoptosis rate, mitochondrial membrane potential (MMP), morphologic change, the intracellular Ca2+ content (F340/F380) and the expressions of Bcl-2, Bax and Caspase-3. Additionally, the constituents from tested extracts were analyzed by HPLC-DAD-Q-TOF-MS method. Results: Compared with a positive control, Vitamin E, 10 µg/ml of 95% EtOH extract (HCECA) and 75% EtOH extract (MCECA) can markedly increase the rate of cell survival and enhance the antioxidant enzyme activities of SOD, CAT, increase the levels of GSH, decrease LDH release and the level of ROS, attenuate the intracellular Ca2+ overloading, reduce the cell apoptotic rate and stabilize MMP, down-regulate Bcl-2 expression, up-regulate Bax and caspase-3 expression, and improve the change of cell morphology. The chemical analysis showed that diarylheptanoids and sesquiterpenoids are the major chemicals in tested extracts and the former were richer in HCECA and MCECA than others. Conclusions: These findings indicated that the effects of HCECA and MCECA on inhibiting the cells damage induced by H2O2 in PC12 are better than other extracts from the radix of C. aromatica, and the active constituents with neuroprotective effects consisting in those two active extracts are diarylheptanoids.

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Calycosin-7-O-β-D-glucoside Attenuates OGD/R-Induced Damage by Preventing Oxidative Stress and Neuronal Apoptosis via the SIRT1/FOXO1/PGC-1α Pathway in HT22 Cells

Neural Plasticity ◽

10.1155/2019/8798069 ◽

2019 ◽

Vol 2019 ◽

pp. 1-11

Author(s):

Xiangli Yan ◽

Aiming Yu ◽

Haozhen Zheng ◽

Shengxin Wang ◽

Yingying He ◽

...

Keyword(s):

Oxidative Stress ◽

Neuronal Apoptosis ◽

Ischemia Reperfusion ◽

Glucose Deprivation ◽

Pathological Process ◽

Neuroprotective Effects ◽

Ht22 Cells ◽

Positive Effects ◽

Antioxidant Stress

Neuronal apoptosis induced by oxidative stress is a major pathological process that occurs after cerebral ischemia-reperfusion. Calycosin-7-O-β-D-glucoside (CG) is a representative component of isoflavones in Radix Astragali (RA). Previous studies have shown that CG has potential neuroprotective effects. However, whether CG alleviates neuronal apoptosis through antioxidant stress after ischemia-reperfusion remains unknown. To investigate the positive effects of CG on oxidative stress and apoptosis of neurons, we simulated the ischemia-reperfusion process in vitro using an immortalized hippocampal neuron cell line (HT22) and oxygen-glucose deprivation/reperfusion (OGD/R) model. CG significantly improved cell viability and reduced oxidative stress and neuronal apoptosis. In addition, CG treatment upregulated the expression of SIRT1, FOXO1, PGC-1α, and Bcl-2 and downregulated the expression of Bax. In summary, our findings indicate that CG alleviates OGD/R-induced damage via the SIRT1/FOXO1/PGC-1α signaling pathway. Thus, CG maybe a promising therapeutic candidate for brain injury associated with ischemic stroke.

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Neurotherapeutic Effect of Inula britannica var. Chinensis against H2O2-Induced Oxidative Stress and Mitochondrial Dysfunction in Cortical Neurons

Antioxidants ◽

10.3390/antiox10030375 ◽

2021 ◽

Vol 10 (3) ◽

pp. 375

Author(s):

Jin Young Hong ◽

Hyunseong Kim ◽

Junseon Lee ◽

Wan-Jin Jeon ◽

Seung Ho Baek ◽

...

Keyword(s):

Oxidative Stress ◽

Mitochondrial Dysfunction ◽

Cortical Neurons ◽

Inflammatory Diseases ◽

Neuroprotective Effect ◽

Neuroprotective Effects ◽

Neuronal Viability ◽

Inula Britannica ◽

Oxidative Effects

Inula britannica var. chinensis (IBC) has been used as a traditional medicinal herb to treat inflammatory diseases. Although its anti-inflammatory and anti-oxidative effects have been reported, whether IBC exerts neuroprotective effects and the related mechanisms in cortical neurons remain unknown. In this study, we investigated the effects of different concentrations of IBC extract (5, 10, and 20 µg/mL) on cortical neurons using a hydrogen peroxide (H2O2)-induced injury model. Our results demonstrate that IBC can effectively enhance neuronal viability under in vitro-modeled reaction oxygen species (ROS)-generating conditions by inhibiting mitochondrial ROS production and increasing adenosine triphosphate level in H2O2-treated neurons. Additionally, we confirmed that neuronal death was attenuated by improving the mitochondrial membrane potential status and regulating the expression of cytochrome c, a protein related to cell death. Furthermore, IBC increased the expression of brain-derived neurotrophic factor and nerve growth factor. Furthermore, IBC inhibited the loss and induced the production of synaptophysin, a major synaptic vesicle protein. This study is the first to demonstrate that IBC exerts its neuroprotective effect by reducing mitochondria-associated oxidative stress and improving mitochondrial dysfunction.

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