scholarly journals Neuroprotective effect of selumetinib on acrolein-induced neurotoxicity

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Hui-Ju Huang ◽  
Hsiang-Tsui Wang ◽  
Ting-Yu Yeh ◽  
Bo-Wei Lin ◽  
Young-Ji Shiao ◽  
...  
Keyword(s):  
Cell Death ◽  
Neurodegenerative Diseases ◽  
Neurite Outgrowth ◽  
Cortical Neurons ◽  
Neuroprotective Effect ◽  
Heme Oxygenase 1 ◽  
Interacting Protein ◽  
Erk Phosphorylation ◽  
Cultured Cortical Neurons

AbstractAbnormal accumulation of acrolein, an α, β unsaturated aldehyde has been reported as one pathological cause of the CNS neurodegenerative diseases. In the present study, the neuroprotective effect of selumetinib (a MEK–ERK inhibitor) on acrolein-induced neurotoxicity was investigated in vitro using primary cultured cortical neurons. Incubation of acrolein consistently increased phosphorylated ERK levels. Co-treatment of selumetinib blocked acrolein-induced ERK phosphorylation. Furthermore, selumetinib reduced acrolein-induced increases in heme oxygenase-1 (a redox-regulated chaperone protein) and its transcriptional factor, Nrf-2 as well as FDP-lysine (acrolein-lysine adducts) and α-synuclein aggregation (a pathological biomarker of neurodegeneration). Morphologically, selumetinib attenuated acrolein-induced damage in neurite outgrowth, including neuritic beading and neurite discontinuation. Moreover, selumetinib prevented acrolein-induced programmed cell death via decreasing active caspase 3 (a hallmark of apoptosis) as well as RIP (receptor-interacting protein) 1 and RIP3 (biomarkers for necroptosis). In conclusion, our study showed that selumetinib inhibited acrolein-activated Nrf-2-HO-1 pathway, acrolein-induced protein conjugation and aggregation as well as damage in neurite outgrowth and cell death, suggesting that selumetinib, a MEK–ERK inhibitor, may be a potential neuroprotective agent against acrolein-induced neurotoxicity in the CNS neurodegenerative diseases.

scholarly journals The Study of the Neuroprotective Effect of the Extract from Chelidonium Majus L. in Vitro

2019 ◽  
Vol 4 (2) ◽  
pp. 106-113
Author(s):  
A. Zhalsrai ◽  
L. Ts. Sanzhieva
Keyword(s):  
Cortical Neurons ◽  
Neuroprotective Effect ◽  
Chain Complex ◽  
Luciferase Reporter ◽  
Chelidonium Majus ◽  
Total Alkaloids ◽  
Cultured Cortical Neurons ◽  
Important Challenge ◽  
Lipid Radicals

The protection of neurons from damage and death is an important challenge in the development of treatment of brain ischemia and neurodegenerative diseases. This study aims to investigate protective effect of the extract prepared from Chelidonium majus, which contains total alkaloids. In the present study, we examined antioxidant activity of total alkaloids from Chelidonium majus in vitro. Hydroxyl radical and lipid radicals were detected using spin trapping agents with ESR spectrometer. Chelidonium majus extract exhibited dose-dependent scavenging effects on lipid radicals. Halfmaximal inhibitory concentration (IC50) of the extract was 2.96 mg/ml, whereas for hydroxyl radicals it was 55.13 mg/ ml. These results showed that extract of Chelidonium majus is partly inhibited free radicals. Antioxidant effects of this extract were further demonstrated by protecting enzyme activity of the mitochondrial respiratory electron transport chain (complex I) in isolated brain mitochondrial dysfunction induced by MDA. However, it did not change the decreased level of complex II, and malate dehydrogenase (MDH) in a concentration of 12 and 25 mg/ml. Here, we examined the neuroprotective effect of the extract from Chelidonium majus against oxidative stress in cultured cortical neurons, using MTT. We found that pretreatment with the extract of Chelidonium majus (0.05 and 0.5 mg/ml) significantly inhibited H2O2-induced cell death in cortical neurons.Furthermore, the use of a luciferase reporter (ARE-luc) assay showed that extract from Chelidonium majus activates protective signaling pathway in primary cortical neurons through ARE/Nrf2 pathway.Together, this suggests that total alkaloids from Chelidonium majus may be neuroprotective by increasing anti-oxidant gene expression.

scholarly journals Physalis alkekengi L. var. francheti alleviates neuronal cell death caused by activated microglia in vitro

2021 ◽  
Vol 64 (1) ◽  
Author(s):  
Byoung Hee Park ◽  
Oh Wook Kwon ◽  
In Sung Kim ◽  
Hae Min Lee ◽  
Yeon Jin Roh ◽  
...  
Keyword(s):  
Cell Death ◽  
Neurodegenerative Diseases ◽  
Neuronal Cell Death ◽  
Neuronal Cell ◽  
Ethanol Extract ◽  
No Production ◽  
Potential Candidate ◽  
Activated Microglia ◽  
Erk Phosphorylation

AbstractMicroglia are the macrophages that reside in the brain. Activated microglia induces further activation of astrocytes and neuronal cells for mounting an immune response. However, activated microglia release neurotoxic mediators causing neuroinflammation, which is associated with chronic etiology of neurodegenerative diseases. We investigated the effect of ethanol extract of Physalis alkekengi L. var. francheti fruit (PAFE) on neuronal cell death mediated by activated microglia. PAFE decreased NO production and IL-6 secretion in LPS-stimulated BV-2 and primary microglial cells without reducing cell viability. Consistently, treatment with PAFE decreased iNOS and COX-2 expression and ERK phosphorylation in LPS-stimulated BV-2 cells. Finally, apoptosis of N2a cells grown in conditioned media prepared from LPS-stimulated BV-2 cells containing PAFE was inhibited via downregulation of the Bax/Bcl-2 ratio. Taken together, PAFE alleviates neuronal cell death by reducing neurotoxic mediators such as NO and IL-6 from activated microglia. Therefore, it could be a potential candidate to treat neurodegenerative diseases caused by chronic neuroinflammation.

scholarly journals Protective Effect of Osmundacetone against Neurological Cell Death Caused by Oxidative Glutamate Toxicity

Biomolecules ◽  
2021 ◽  
Vol 11 (2) ◽  
pp. 328
Author(s):  
Tuy An Trinh ◽  
Young Hye Seo ◽  
Sungyoul Choi ◽  
Jun Lee ◽  
Ki Sung Kang
Keyword(s):  
Oxidative Stress ◽  
Cell Death ◽  
Defense Mechanism ◽  
Neuroprotective Effect ◽  
Glutamate Release ◽  
Chromatin Condensation ◽  
Critical Role ◽  
Glutamate Toxicity ◽  
Heme Oxygenase 1 ◽  
Brain Functions

Oxidative stress is one of the main causes of brain cell death in neurological disorders. The use of natural antioxidants to maintain redox homeostasis contributes to alleviating neurodegeneration. Glutamate is an excitatory neurotransmitter that plays a critical role in many brain functions. However, excessive glutamate release induces excitotoxicity and oxidative stress, leading to programmed cell death. Our study aimed to evaluate the effect of osmundacetone (OAC), isolated from Elsholtzia ciliata (Thunb.) Hylander, against glutamate-induced oxidative toxicity in HT22 hippocampal cells. The effect of OAC treatment on excess reactive oxygen species (ROS), intracellular calcium levels, chromatin condensation, apoptosis, and the expression level of oxidative stress-related proteins was evaluated. OAC showed a neuroprotective effect against glutamate toxicity at a concentration of 2 μM. By diminishing the accumulation of ROS, as well as stimulating the expression of heat shock protein 70 (HSP70) and heme oxygenase-1 (HO-1), OAC triggered the self-defense mechanism in neuronal cells. The anti-apoptotic effect of OAC was demonstrated through its inhibition of chromatin condensation, calcium accumulation, and reduction of apoptotic cells. OAC significantly suppressed the phosphorylation of mitogen-activated protein kinases (MAPKs), including c-Jun NH2-terminal kinase (JNK), extracellular signal-regulated kinase (ERK), and p38 kinases. Thus, OAC could be a potential agent for supportive treatment of neurodegenerative diseases.

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

Antioxidants ◽  
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.

scholarly journals Mumijo Traditional Medicine: Fossil Deposits from Antarctica (Chemical Composition and Beneficial Bioactivity)

2011 ◽  
Vol 2011 ◽  
pp. 1-8 ◽  
Author(s):  
Anna Aiello ◽  
Ernesto Fattorusso ◽  
Marialuisa Menna ◽  
Rocco Vitalone ◽  
Heinz C. Schröder ◽  
...  
Keyword(s):  
Chemical Composition ◽  
Traditional Medicine ◽  
Cortical Neurons ◽  
Neuroprotective Effect ◽  
Amyloid Peptide ◽  
Neuroprotective Activity ◽  
Antiallergic Activity ◽  
Neuronal Pc12 Cells ◽  
Biomedical Potential

Mumijo is a widely used traditional medicine, especially in Russia, Altai Mountains, Mongolia, Iran Kasachstan and in Kirgistan. Mumijo preparations have been successfully used for the prevention and treatment of infectious diseases; they display immune-stimulating and antiallergic activity as well. In the present study, we investigate the chemical composition and the biomedical potential of a Mumijo(-related) product collected from the Antarctica. The yellow material originates from the snow petrels,Pagodroma nivea. Extensive purification and chemical analysis revealed that the fossil samples are a mixture of glycerol derivatives.In vitroexperiments showed that the Mumijo extract caused in cortical neurons a strong neuroprotective effect against the apoptosis-inducing amyloid peptide fragmentβ-fragment 25–35 (Aβ25–35). In addition, the fraction rich in glycerol ethers/wax esters displayed a significant growth-promoting activity in permanent neuronal PC12 cells. It is concluded that this new Mumijo preparation has distinct and marked neuroprotective activity, very likely due to the content of glycerol ether derivatives.

scholarly journals Heme induces programmed necrosis on macrophages through autocrine TNF and ROS production

Blood ◽  
2012 ◽  
Vol 119 (10) ◽  
pp. 2368-2375 ◽  
Author(s):  
Guilherme B. Fortes ◽  
Leticia S. Alves ◽  
Rosane de Oliveira ◽  
Fabianno F. Dutra ◽  
Danielle Rodrigues ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Cell Death ◽  
Critical Role ◽  
Membrane Integrity ◽  
Iron Chelation ◽  
Heme Oxygenase 1 ◽  
Cytotoxic Effects ◽  
Interacting Protein ◽  
Free Heme ◽  
Necrosis Factor

Abstract Diseases that cause hemolysis or myonecrosis lead to the leakage of large amounts of heme proteins. Free heme has proinflammatory and cytotoxic effects. Heme induces TLR4-dependent production of tumor necrosis factor (TNF), whereas heme cytotoxicity has been attributed to its ability to intercalate into cell membranes and cause oxidative stress. We show that heme caused early macrophage death characterized by the loss of plasma membrane integrity and morphologic features resembling necrosis. Heme-induced cell death required TNFR1 and TLR4/MyD88-dependent TNF production. Addition of TNF to Tlr4−/− or to Myd88−/− macrophages restored heme-induced cell death. The use of necrostatin-1, a selective inhibitor of receptor-interacting protein 1 (RIP1, also known as RIPK1), or cells deficient in Rip1 or Rip3 revealed a critical role for RIP proteins in heme-induced cell death. Serum, antioxidants, iron chelation, or inhibition of c-Jun N-terminal kinase (JNK) ameliorated heme-induced oxidative burst and blocked macrophage cell death. Macrophages from heme oxygenase-1 deficient mice (Hmox1−/−) had increased oxidative stress and were more sensitive to heme. Taken together, these results revealed that heme induces macrophage necrosis through 2 synergistic mechanisms: TLR4/Myd88-dependent expression of TNF and TLR4-independent generation of ROS.

scholarly journals SGTA associates with intracellular aggregates in neurodegenerative diseases.

2020 ◽  
Author(s):  
Shun Kubota ◽  
Hiroshi Doi ◽  
Shigeru Koyano ◽  
Kenichi Tanaka ◽  
Shingo Ikeda ◽  
...  
Keyword(s):  
Neurodegenerative Diseases ◽  
Molecular Mechanisms ◽  
In Vitro Study ◽  
Interacting Proteins ◽  
Interacting Protein ◽  
Cytoplasmic Inclusions ◽  
Specific Proteins ◽  
Intracellular Aggregates ◽  
Polyq Diseases

Abstract Intracellular aggregates are a common pathological hallmark of neurodegenerative diseases such as polyglutamine (polyQ) diseases, amyotrophic lateral sclerosis (ALS), Parkinson’s disease (PD), and multiple system atrophy (MSA). Aggregates are mainly formed by aberrant disease-specific proteins and are accompanied by accumulation of other aggregate-interacting proteins. Although aggregate-interacting proteins have been considered to modulate the formation of aggregates and to be involved in molecular mechanisms of disease progression, the components of aggregate-interacting proteins remain unknown. In this study, we showed that small glutamine-rich tetratricopeptide repeat-containing protein alfa (SGTA) is an aggregate-interacting protein in neurodegenerative diseases. Immunohistochemistry showed that SGTA interacted with intracellular aggregates in Huntington disease (HD) cell models and neurons of HD model mice. We also revealed that SGTA colocalized with intracellular aggregates in postmortem brains of patients with polyQ diseases including spinocerebellar ataxia (SCA)1, SCA2, SCA3, and dentatorubral–pallidoluysian atrophy. In addition, SGTA colocalized with glial cytoplasmic inclusions in the brains of MSA patients, whereas no accumulation of SGTA was observed in neurons of PD and ALS patients. In vitro study showed that SGTA bound to polyQ aggregates through its C-terminal domain and SGTA overexpression reduced intracellular aggregates. These results suggest that SGTA may play a role in the formation of aggregates and may act as potential modifier of molecular pathological mechanisms of polyQ diseases and MSA.

scholarly journals Effects of Carbazole Derivatives on Neurite Outgrowth and Hydrogen Peroxide-Induced Cytotoxicity in Neuro2a Cells

Molecules ◽  
2019 ◽  
Vol 24 (7) ◽  
pp. 1366 ◽  
Author(s):  
Yoshiko Furukawa ◽  
Atsushi Sawamoto ◽  
Mizuki Yamaoka ◽  
Makiko Nakaya ◽  
Yuhzo Hieda ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Hydrogen Peroxide ◽  
Cell Death ◽  
Neurite Outgrowth ◽  
Akt Signaling ◽  
Akt Signaling Pathway ◽  
Anti Oxidant ◽  
Neuro2a Cells ◽  
Cerebral Ischemic

Many studies have demonstrated that oxidative stress plays an important role in several ailments including neurodegenerative diseases and cerebral ischemic injury. Previously we synthesized some carbazole compounds that have anti-oxidant ability in vitro. In this present study, we found that one of these 22 carbazole compounds, compound 13 (3-ethoxy-1-hydroxy-8- methoxy-2-methylcarbazole-5-carbaldehyde), had the ability to protect neuro2a cells from hydrogen peroxide-induced cell death. It is well known that neurite loss is one of the cardinal features of neuronal injury. Our present study revealed that compound 13 had the ability to induce neurite outgrowth through the PI3K/Akt signaling pathway in neuro2a cells. These findings suggest that compound 13 might exert a neurotrophic effect and thus be a useful therapy for the treatment of brain injury.

scholarly journals Neuroprotective Effect of Bergamot Juice in 6-OHDA-Induced SH-SY5Y Cell Death, an In Vitro Model of Parkinson’s Disease

Pharmaceutics ◽  
2020 ◽  
Vol 12 (4) ◽  
pp. 326 ◽  
Author(s):  
Nadia Ferlazzo ◽  
Santa Cirmi ◽  
Alessandro Maugeri ◽  
Caterina Russo ◽  
Giovanni Enrico Lombardo ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Cell Death ◽  
Nuclear Translocation ◽  
Neuroprotective Effect ◽  
Neuroblastoma Cells ◽  
Specific Cell ◽  
Protective Effects ◽  
Human Neuroblastoma

Much evidence suggests that both oxidative stress and apoptosis play a key role in the pathogenesis of Parkinson’s disease (PD). The present study aims to evaluate the protective effect of bergamot juice (BJ) against 6-hydroxydopamine (6-OHDA)- or H2O2-induced cell death. Treatment of differentiated SH-SY5Y human neuroblastoma cells with 6-OHDA or H2O2 resulted in cell death that was significantly reduced by the pre-treatment with BJ. The protective effects of BJ seem to correlate with the reduction of intracellular reactive oxygen species and nitric oxide generation caused by 6-OHDA or H2O2. BJ also attenuated mitochondrial dysfunction, caspase-3 activation, imbalance of pro- and anti-apoptotic proteins, MAPKs activation and reduced NF-ĸB nuclear translocation evoked by neurotoxic agents. Additionally, BJ exhibited excellent antioxidant capability in cell-free assays. Collectively, our results suggest that BJ exerts neuroprotective effect through the interplay with specific cell targets and its antioxidant activity, making it worthy of consideration for the management of neurodegenerative diseases.

scholarly journals PrP is a central player in toxicity mediated by soluble aggregates of neurodegeneration-causing proteins

2019 ◽  
Vol 139 (3) ◽  
pp. 503-526 ◽  
Author(s):  
Grant T. Corbett ◽  
Zemin Wang ◽  
Wei Hong ◽  
Marti Colom-Cadena ◽  
Jamie Rose ◽  
...  
Keyword(s):  
Neurodegenerative Diseases ◽  
Cortical Neurons ◽  
Lewy Bodies ◽  
Public Health Problem ◽  
Therapeutic Targeting ◽  
Neuronal Proteins ◽  
Neuritic Dystrophy ◽  
Soluble Aggregates ◽  
Blocking Antibodies

AbstractNeurodegenerative diseases are an enormous public health problem, affecting tens of millions of people worldwide. Nearly all of these diseases are characterized by oligomerization and fibrillization of neuronal proteins, and there is great interest in therapeutic targeting of these aggregates. Here, we show that soluble aggregates of α-synuclein and tau bind to plate-immobilized PrP in vitro and on mouse cortical neurons, and that this binding requires at least one of the same N-terminal sites at which soluble Aβ aggregates bind. Moreover, soluble aggregates of tau, α-synuclein and Aβ cause both functional (impairment of LTP) and structural (neuritic dystrophy) compromise and these deficits are absent when PrP is ablated, knocked-down, or when neurons are pre-treated with anti-PrP blocking antibodies. Using an all-human experimental paradigm involving: (1) isogenic iPSC-derived neurons expressing or lacking PRNP, and (2) aqueous extracts from brains of individuals who died with Alzheimer’s disease, dementia with Lewy bodies, and Pick’s disease, we demonstrate that Aβ, α-synuclein and tau are toxic to neurons in a manner that requires PrPC. These results indicate that PrP is likely to play an important role in a variety of late-life neurodegenerative diseases and that therapeutic targeting of PrP, rather than individual disease proteins, may have more benefit for conditions which involve the aggregation of more than one protein.

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