scholarly journals Multi-Target Effects of Novel Synthetic Coumarin Derivatives Protecting Aβ-GFP SH-SY5Y Cells against Aβ Toxicity

Cells ◽  
2021 ◽  
Vol 10 (11) ◽  
pp. 3095
Author(s):  
Ching-Chia Huang ◽  
Kuo-Hsuan Chang ◽  
Ya-Jen Chiu ◽  
Yi-Ru Chen ◽  
Tsai-Hui Lung ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Neuroblastoma Cell ◽  
Amyloid Β ◽  
B Cell Lymphoma ◽  
Camp Response Element Binding ◽  
Coumarin Derivatives ◽  
Neuroprotective Effects ◽  
Caspase 1 ◽  
High Affinity Receptor ◽  
Tropomyosin Related Kinase B

Alzheimer’s disease (AD) is a common neurodegenerative disease presenting with progressive memory and cognitive impairments. One of the pathogenic mechanisms of AD is attributed to the aggregation of misfolded amyloid β (Aβ), which induces neurotoxicity by reducing the expression of brain-derived neurotrophic factor (BDNF) and its high-affinity receptor tropomyosin-related kinase B (TRKB) and increasing oxidative stress, caspase-1, and acetylcholinesterase (AChE) activities. Here, we have found the potential of two novel synthetic coumarin derivatives, ZN014 and ZN015, for the inhibition of Aβ and neuroprotection in SH-SY5Y neuroblastoma cell models for AD. In SH-SY5Y cells expressing the GFP-tagged Aβ-folding reporter, both ZN compounds reduced Aβ aggregation, oxidative stress, activities of caspase-1 and AChE, as well as increased neurite outgrowth. By activating TRKB-mediated extracellular signal-regulated kinase (ERK) and AKT serine/threonine kinase 1 (AKT) signaling, these two ZN compounds also upregulated the cAMP-response-element binding protein (CREB) and its downstream BDNF and anti-apoptotic B-cell lymphoma 2 (BCL2). Knockdown of TRKB attenuated the neuroprotective effects of ZN014 and ZN015. A parallel artificial membrane permeability assay showed that ZN014 and ZN015 could be characterized as blood–brain barrier permeable. Our results suggest ZN014 and ZN015 as novel therapeutic candidates for AD and demonstrate that ZN014 and ZN015 reduce Aβ neurotoxicity via pleiotropic mechanisms.

scholarly journals LongShengZhi Capsule Attenuates Alzheimer-Like Pathology in APP/PS1 Double Transgenic Mice by Reducing Neuronal Oxidative Stress and Inflammation

2020 ◽  
Vol 12 ◽  
Author(s):  
Zequn Yin ◽  
Xuerui Wang ◽  
Shihong Zheng ◽  
Peichang Cao ◽  
Yuanli Chen ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Transgenic Mice ◽  
Amyloid Β ◽  
B Cell Lymphoma ◽  
Acanthopanax Senticosus ◽  
Neuroprotective Effects ◽  
Long Term Treatment ◽  
Double Transgenic Mice ◽  
The Brain

Alzheimer’s disease (AD) is the most common form of dementia in the elderly. It may be caused by oxidative stress, inflammation, and cerebrovascular dysfunctions in the brain. LongShengZhi Capsule (LSZ), a traditional Chinese medicine, has been approved by the China Food and Drug Administration for treatment of patients with cardiovascular/cerebrovascular disease. LSZ contains several neuroprotective ingredients, including Hirudo, Astmgali Radix, Carthami Flos (Honghua), Persicae Semen (Taoren), Acori Tatarinowii Rhizoma (Shichangpu), and Acanthopanax Senticosus (Ciwujia). In this study, we aimed to determine the effect of LSZ on the AD process. Double transgenic mice expressing the amyloid-β precursor protein and mutant human presenilin 1 (APP/PS1) to model AD were treated with LSZ for 7 months starting at 2 months of age. LSZ significantly improved the cognition of the mice without adverse effects, indicating its high degree of safety and efficacy after a long-term treatment. LSZ reduced AD biomarker Aβ plaque accumulation by inhibiting β-secretase and γ-secretase gene expression. LSZ also reduced p-Tau expression, cell death, and inflammation in the brain. Consistently, in vitro, LSZ ethanol extract enhanced neuronal viability by reducing L-glutamic acid-induced oxidative stress and inflammation in HT-22 cells. LSZ exerted antioxidative effects by enhancing superoxide dismutase and glutathione peroxidase expression, reduced Aβ accumulation by inhibiting β-secretase and γ-secretase mRNA expression, and decreased p-Tau level by inhibiting NF-κB-mediated inflammation. It also demonstrated neuroprotective effects by regulating the Fas cell surface death receptor/B-cell lymphoma 2/p53 pathway. Taken together, our study demonstrates the antioxidative stress, anti-inflammatory, and neuroprotective effects of LSZ in the AD-like pathological process and suggests it could be a potential medicine for AD treatment.

Berberine nanoencapsulation attenuates hallmarks of scoplomine induced Alzheimer's-like disease in rats

2020 ◽  
Vol 15 ◽  
Author(s):  
Samar R. Saleh ◽  
Mariam M. Abady ◽  
Mohammed Nofal ◽  
Nashwa W. Yassa ◽  
Mohamed S. Abdel-latif ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Histopathological Examination ◽  
Memory Function ◽  
Amyloid Β ◽  
Active Pharmaceutical Ingredient ◽  
Isoquinoline Alkaloid ◽  
Drug Uptake ◽  
Male Rats ◽  
Morris Water Maze Test ◽  
Neuroprotective Effects

Background: Berberine (BBR), an isoquinoline alkaloid, acts as a multipotent active pharmaceutical ingredient to counteract several types of dementia based on its numerous pharmacological actions including antioxidant, antiinflammatory, cholesterol-lowering effect, and inhibition of Aβ production and AChE. However, BBR suffers from poor absorption, bioavailability and brain drug uptake. The present study is directed for the formulation and characterization of Chitosan BBR-nanoparticles (BBR-NPs) as well as the estimation of its neuroprotective effects against scopolamine induced cognitive impairments. Methods: BBR-NPs were formulated using ionic gelation method and tripolyphosphate was chosen as a cross linker. Nanoparticles size, zeta potential, encapsulation efficiency and releasing profile were estimated. To investigate the neuroprotective effects, adult fifty six Wistar male rats were randomly distributed into: three control groups, received saline, polyethylene glycol or chitosan- NPs respectively; induced group, received scopolamine (2 mg/ kg, i.p.) and three treated groups were orally administrated BBR (50 mg/ kg), BBR- NP (7 mg/ kg) and donepezil (2.25 mg/ kg, as positive control) followed by scopolamine injection after 40 min, daily for 4 weeks. Morris water maze test, oxidative stress parameters, cholinergic and amyloid-β processing intermediates as well as neuroplasticity markers and histopathological examination were assessed. Results: Our results showed that BBR- NPs were better than BBR and donepezil as BBR- NPs were powerful inhibitory ligands toward AChE and Aβ42 formation and significantly down regulated Tau, iNOS and BACE gene expression in rats’ hippocampus. BBR-NPs administration, at 1/6 of BBR therapeutic recommended dose, significantly improved learning and memory function. This could be accredited to the diminution of oxidative stress and amyloid-β toxicity in addition to the improvement of the neuroplasticity markers. Conclusions: The enhancing effect of BBR- NPs could be related to the enhancing of its bioavailability, absorption and brain drug uptake which need more investigation in future work.

scholarly journals In vitroscreening of neuroprotective activity of Indian medicinal plantWithania somnifera

2017 ◽  
Vol 6 ◽  
Author(s):  
Manjeet Singh ◽  
Charles Ramassamy
Keyword(s):  
Neuroblastoma Cell ◽  
Amyloid Β ◽  
Acetylcholinesterase Activity ◽  
Neuroprotective Activity ◽  
Great Promise ◽  
Human Neuroblastoma Cell ◽  
Amyloid Β Peptide ◽  
Aβ Peptide ◽  
Neuroprotective Effects ◽  
Human Neuroblastoma

AbstractCanine cognitive dysfunction (CCD) is an age-dependent neurodegenerative condition characterised by changes in decline in learning and memory patterns. The neurodegenerative features of CCD in ageing dogs and cats are similar to human ageing and Alzheimer's disease (AD). Discovering neuroprotective disease-modifying therapies against CCD and AD is a major challenge. Strong evidence supports the role of amyloid β peptide deposition and oxidative stress in the pathophysiology of CCD and AD. In both the human and canine brain, oxidative damage progressively increases with age. Dietary antioxidants from natural sources hold a great promise in halting the progression of CCD and AD.Withania somnifera(WS), an Ayurvedic tonic medicine, also known as ‘Indian ginseng’ orashwagandhahas a long history of use in memory-enhancing therapy but there is a dearth of studies on its neuroprotective effects. The objective of this study was to investigate whetherWSextract can protect against Aβ peptide- and acrolein-induced toxicity. We demonstrated that treatment withWSextract significantly protected the human neuroblastoma cell line SK-N-SH against Aβ peptide and acrolein in various cell survival assays. Furthermore, treatment withWSextract significantly reduced the generation of reactive oxygen species in SK-N-SH cells. Finally, our results showed thatWSextract is also a potent inhibitor of acetylcholinesterase activity. Thus, our initial findings indicate thatWSextract may act as an antioxidant and cholinergic modulator and may have beneficial effects in CCD and AD therapy.

Neuroprotective effects of N-adamantyl-4-methylthiazol-2-amine against amyloid β-induced oxidative stress in mouse hippocampus

2017 ◽  
Vol 128 ◽  
pp. 22-28 ◽  
Author(s):  
Jiae Kim ◽  
Chang Hun Cho ◽  
Hoh-Gyu Hahn ◽  
Soo-Young Choi ◽  
Sung-Woo Cho
Keyword(s):  
Oxidative Stress ◽  
Amyloid Β ◽  
Neuroprotective Effects ◽  
Mouse Hippocampus

scholarly journals Ginsenoside Rh1 Exerts Neuroprotective Effects by Activating the PI3K/Akt Pathway in Amyloid-β Induced SH-SY5Y Cells

2021 ◽  
Vol 11 (12) ◽  
pp. 5654
Author(s):  
Miey Park ◽  
So-Hyeun Kim ◽  
Hae-Jeung Lee
Keyword(s):  
Oxidative Stress ◽  
Cell Death ◽  
Signaling Pathways ◽  
Neurodegenerative Disorders ◽  
Neurodegenerative Disorder ◽  
Amyloid Β ◽  
Tau Proteins ◽  
Neuroprotective Effects ◽  
Human Neuroblastoma ◽  
Β Amyloid

Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by the accumulation of β-amyloid plaques and hyperphosphorylated tau proteins in the brain. Cell signaling pathways such as PI3K/Akt are known to play an essential role in regulating cell survival, motility, transcription, metabolism, and progression of the cell cycle. Recent studies demonstrated that the disruption of these signaling pathways in neurodegenerative disorders leads to oxidative stress and cell death. Targeting these altered signaling pathways could be considered as the therapeutic approach for neurodegenerative disorders. Ginsenoside Rh1 is known to provide beneficial effects in various diseases such as cancer, diabetes, and inflammation. In this study, human neuroblastoma SH-SY5Y cells were treated with the β-amyloid oligomers alone or in combination with ginsenoside Rh1. We observed that ginsenoside Rh1 was able to attenuate β-amyloid induced oxidative stress and cell death by activating the PI3K/Akt signaling pathway. Based on these findings, we suggest that ginsenoside Rh1 might be an efficacious therapeutic agent for AD.

scholarly journals Flavones 7,8-DHF, Quercetin, and Apigenin Against Tau Toxicity via Activation of TRKB Signaling in ΔK280 TauRD-DsRed SH-SY5Y Cells

2021 ◽  
Vol 13 ◽  
Author(s):  
Ni-Ni Chiang ◽  
Te-Hsien Lin ◽  
Yu-Shan Teng ◽  
Ying-Chieh Sun ◽  
Kuo-Hsuan Chang ◽  
...  
Keyword(s):  
Cellular Response ◽  
Memory Loss ◽  
Treatment Strategies ◽  
Camp Response Element Binding ◽  
Neuroprotective Effects ◽  
Downstream Signaling ◽  
Element Binding Protein ◽  
Tropomyosin Related Kinase B ◽  
New Treatment ◽  
Tau Aggregation

Alzheimer’s disease (AD) is a progressive neurodegenerative disease with memory loss and cognitive decline. Neurofibrillary tangles (NFTs) formed by hyperphosphorylated Tau protein are one of the pathological hallmarks of several neurodegenerative diseases including AD. Heat shock protein family B (small) member 1 (HSPB1) is a molecular chaperone that promotes the correct folding of other proteins in response to environmental stress. Nuclear factor erythroid 2-like 2 (NRF2), a redox-regulated transcription factor, is the master regulator of the cellular response to excess reactive oxygen species. Tropomyosin-related kinase B (TRKB) is a membrane-bound receptor that, upon binding brain-derived neurotrophic factor (BDNF), phosphorylates itself to initiate downstream signaling for neuronal survival and axonal growth. In this study, four natural flavones such as 7,8-dihydroxyflavone (7,8-DHF), wogonin, quercetin, and apigenin were evaluated for Tau aggregation inhibitory activity and neuroprotection in SH-SY5Y neuroblastoma. Among the tested flavones, 7,8-DHF, quercetin, and apigenin reduced Tau aggregation, oxidative stress, and caspase-1 activity as well as improved neurite outgrowth in SH-SY5Y cells expressing ΔK280 TauRD-DsRed folding reporter. Treatments with 7,8-DHF, quercetin, and apigenin rescued the reduced HSPB1 and NRF2 and activated TRKB-mediated extracellular signal-regulated kinase (ERK) signaling to upregulate cAMP-response element binding protein (CREB) and its downstream antiapoptotic BCL2 apoptosis regulator (BCL2). Knockdown of TRKB attenuated the neuroprotective effects of these three flavones. Our results suggest 7,8-DHF, quercetin, and apigenin targeting HSPB1, NRF2, and TRKB to reduce Tau aggregation and protect cells against Tau neurotoxicity and may provide new treatment strategies for AD.

scholarly journals Lycopene Protects Cortical Neurons via Oxidative Stress-mediated ΔN-Bcl-xL Formation (FS05-08-19)

2019 ◽  
Vol 3 (Supplement_1) ◽  
Author(s):  
Allison Stumpf ◽  
Katheryn Broman ◽  
Katelyn Senkus ◽  
Libo Tan ◽  
Kristi Crowe-White ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Hydrogen Peroxide ◽  
Cortical Neurons ◽  
Antioxidant Properties ◽  
B Cell Lymphoma ◽  
Nutritional Intervention ◽  
Redox Status ◽  
Neuroprotective Effects ◽  
Protein Levels ◽  
Funding Sources

Abstract Objectives B-cell lymphoma-extra large (Bcl-xL) is a protein found in the mitochondrial membrane with anti-apoptotic properties. Bcl-xL has demonstrated neuroprotective effects by enhancing mitochondrial function. However, during oxidative stress, Bcl-xL undergoes cleavage to form pro-cell death ∆N-Bcl-xL. Accumulation of ∆N-Bcl-xL causes abnormal mitochondrial channel activity associated with neuronal death. Therefore, strategies that prevent formation of ∆N-Bcl-xL protect the brain. In this study, we hypothesize that cleavage of Bcl-xL can be controlled by nutritional intervention. We test if treatment with lycopene, a potent antioxidant with neuroprotective effects, can protect primary neurons via improving intracellular redox status by reducing production of ∆N-Bcl-xL. Methods Primary cortical neurons were treated with lycopene, hydrogen peroxide (a ROS donor), or both. Levels of superoxide, cell viability and cytotoxicity, and protein levels of Bcl-xL and ∆N-Bcl-xL were quantified. Results Hydrogen peroxide increased cytotoxicity while treatment with lycopene protected oxidative stress-induced cortical death. Lycopene prevented N-terminal cleavage of Bcl-xL and thus inhibited formation of ∆N-Bcl-xL. Conclusions These data show that the formation of ∆N-Bcl-xL is induced in part by reactive oxygen species and high levels of oxidative stress. The antioxidant properties of lycopene help reduce oxidative stress and prevent cleavage of Bcl-xL to ∆N-Bcl-xL, thus maintaining an anti-apoptotic environment. Funding Sources RG14811.

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

2018 ◽  
Vol 21 (8) ◽  
pp. 571-582 ◽  
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.

Berberine Alleviates Amyloid-beta Pathogenesis Via Activating LKB1/AMPK Signaling in the Brain of APP/PS1 Transgenic Mice

2019 ◽  
Vol 19 (5) ◽  
pp. 342-348 ◽  
Author(s):  
Zhi-You Cai ◽  
Chuan-Ling Wang ◽  
Tao-Tao Lu ◽  
Wen-Ming Yang
Keyword(s):  
Transgenic Mice ◽  
Western Blotting ◽  
Amyloid Β ◽  
Adenosine Monophosphate ◽  
Camp Response Element Binding ◽  
Enzyme Linked Immunosorbent Assay ◽  
Synaptic Density ◽  
Ampk Signaling ◽  
The Brain ◽  
Post Synaptic Density

Background:Liver kinase B1 (LKB1)/5’-adenosine monophosphate-activated protein kinase (AMPK) signaling, a metabolic checkpoint, plays a neuro-protective role in the pathogenesis of Alzheimer’s disease (AD). Amyloid-β (Aβ) acts as a classical biomarker of AD. The aim of the present study was to explore whether berberine (BBR) activates LKB1/AMPK signaling and ameliorates Aβ pathology.Methods:The Aβ levels were detected using enzyme-linked immunosorbent assay and immunohistochemistry. The following biomarkers were measured by Western blotting: phosphorylated (p-) LKB1 (Ser334 and Thr189), p-AMPK (AMPKα and AMPKβ1), synaptophysin, post-synaptic density protein 95 and p-cAMP-response element binding protein (p-CREB). The glial fibrillary acidic protein (GFAP) was determined using Western blotting and immunohistochemistry.Results:BBR inhibited Aβ expression in the brain of APP/PS1 mice. There was a strong up-regulation of both p-LKB1 (Ser334 and Thr189) and p-AMPK (AMPKα and AMPKβ1) in the brains of APP/PS1 transgenic mice after BBR-treatment (P<0.01). BBR promoted the expression of synaptophysin, post-synaptic density protein 95 and p-CREB(Ser133) in the AD brain, compared with the model mice.Conclusion:BBR alleviates Aβ pathogenesis and rescues synapse damage via activating LKB1/AMPK signaling in the brain of APP/PS1 transgenic mice.

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