scholarly journals Enantioselective Synthesis and Pharmacological Evaluation of Aza-CGP37157–Lipoic Acid Hybrids for the Treatment of Alzheimer’s Disease

Antioxidants ◽  
2022 ◽  
Vol 11 (1) ◽  
pp. 112
Author(s):  
Ángel Cores ◽  
Patrycja Michalska ◽  
José Miguel Pérez ◽  
Enrique Crisman ◽  
Clara Gómez ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Single Molecule ◽  
Lipoic Acid ◽  
Cell Model ◽  
Neuroprotective Effect ◽  
Neuroblastoma Cells ◽  
Hybrid Structure ◽  
Neuroprotective Activity ◽  
Nitrite Production ◽  
Diastereoselective Reduction

Hybrids based on an aza-analogue of CGP37157, a mitochondrial Na+/Ca2+ exchanger antagonist, and lipoic acid were obtained in order to combine in a single molecule the antioxidant and NRF2 induction properties of lipoic acid and the neuroprotective activity of CGP37157. The four possible enantiomers of the hybrid structure were synthesized by using as the key step a fully diastereoselective reduction induced by Ellman’s chiral auxiliary. After computational druggability studies that predicted good ADME profiles and blood–brain permeation for all compounds, the DPPH assay showed moderate oxidant scavenger capacity. Following a cytotoxicity evaluation that proved the compounds to be non-neurotoxic at the concentrations tested, they were assayed for NRF2 induction capacity and for anti-inflammatory properties and measured by their ability to inhibit nitrite production in the lipopolysaccharide-stimulated BV2 microglial cell model. Moreover, the compounds were studied for their neuroprotective effect in a model of oxidative stress achieved by treatment of SH-SY5Y neuroblastoma cells with the rotenone–oligomycin combination and also in a model of hyperphosphorylation induced by treatment with okadaic acid. The stereocenter configuration showed a critical influence in NRF2 induction properties, and also in the neuroprotection against oxidative stress experiment, leading to the identification of the compound with S and R configuration as an interesting hit with a good neuroprotective profile against oxidative stress and hyperphosphorylation, together with a relevant anti-neuroinflammatory activity. This interesting multitarget profile will be further characterized in future work.

scholarly journals Artemisinin Attenuated Oxidative Stress and Apoptosis by Inhibiting Autophagy in MPP+-treated SH-SY5Y Cell 

2020 ◽  
Author(s):  
Junqiang Yan ◽  
Hongxia Ma ◽  
Xiaoyi Lai ◽  
Jiannan Wu ◽  
Anran Liu ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Dopaminergic Neurons ◽  
Artemisia Annua ◽  
Cell Model ◽  
Neuroprotective Effect ◽  
Critical Role ◽  
Neuroprotective Effects ◽  
Pre Treatment

Abstract Background Parkinson's disease (PD) is the second most common neurodegenerative disease after Alzheimer's. The drugs currently used to treat PD cannot inhibit the development of PD, and long-term use produces severe drug resistance and adverse reaction. Artemisinin (ART) is an active ingredient of Artemisia annua and has a neuroprotective effect, but the mechanism is still unclear. This study was designed to investigate the neuroprotective effect of ART in MPP+-treated SH-SY5Y cells. Results There was no significant cytotoxicity when the ART concentration was under. 40μM. The 20μM ART for 24h could increase the cell viability by reducing oxidative stress and cell apoptosis in MPP+-treated SH-SY5Y cell. In addition, immunoblot and immunofluorescence results showed that MPP+ treatment increased the expression of Beclin1, LC3II/LC3I and decreased the expression of P62, while ART can reverse the changes caused by MPP+. Discussion More and more researches reported that ART and its derivates have neuroprotective effects through anti-oxidant and anti-apoptosis. we found that pre-treated cells with 20μM ART for 4h could significantly increase the viability in Parkinson's disease cell model. The oxidative stress and apoptosis were the main reason for the degeneration of dopaminergic neurons, while artemisinin can attenuate oxidative stress and apoptosis in MPP+-lesioned dopaminergic neurons. The levels of autophagy proteins LC3II/I, Beclin1 and P62 also showed that MPP+ increased the autophagy level, and pre-treatment with ART decreased the autophagy level, which may be the pathological mechanism for artemisinin to reduce oxidative stress damage and apoptosis. Conclusions These results indicate that ART exerts a positive effect on MPP+-treated SH-SY5Y cells in terms of anti-oxidative stress and anti-apoptosis. These effects may be related to autophagy. These findings contribute to a better understanding of the critical role of ART in PD treatment.

scholarly journals Neuroprotective Activity of Coptisine fromCoptis chinensis(Franch)

2015 ◽  
Vol 2015 ◽  
pp. 1-9 ◽  
Author(s):  
Thomas Friedemann ◽  
Udo Schumacher ◽  
Yi Tao ◽  
Alexander Kai-Man Leung ◽  
Sven Schröder
Keyword(s):  
Oxidative Stress ◽  
Neuroprotective Effect ◽  
Neuroprotective Activity ◽  
Important Ingredient ◽  
Promising Candidate ◽  
Interacting Protein ◽  
Thioredoxin Interacting Protein ◽  
Chinese Herbal ◽  
Tert Butylhydroperoxide ◽  
Study Results

Coptis chinensisrhizomes (CR) are one important ingredient of traditional Chinese herbal formulas such as San-Huang-Xie-Xin-Tang which is used for treatment of cardiovascular and neurodegenerative diseases. Recent studies suggest that the extract of CR might be a potential therapeutic agent for amelioration of neurological disorders associated with oxidative stress. In the present study we aimed at revealing the main active compound(s) of the CR extract and at investigating the mechanism of action. Four main alkaloids of the CR extract (berberine, coptisine, jatrorrhizine, and palmatine) were selected for this study. Results showed that out of those alkaloids only pretreatment with coptisine significantly attenuated tert-butylhydroperoxide induced reduction of cell viability, increased rate of apoptosis, and declined mitochondrial membrane potential. Elisa assay and quantitative real-time PCR analyses revealed that thioredoxin-interacting protein (TXNIP) gene expression was downregulated by coptisine, which could explain the neuroprotective effect, hypothetically, by strengthening the thioredoxin defense system against oxidative stress and attenuation of apoptosis signal-regulating kinase (Ask1) mediated apoptotic signaling. A comparison between coptisine and CR extract identified coptisine as the main single component responsible for the neuroprotective effect. Based on the results the CR extract and coptisine are promising candidate agents for prevention or improvement of diabetic neuropathy and neurodegenerative disorders.

scholarly journals Neuroprotective Effect of Cyclo-(L-Pro-L-Phe) Isolated from the Jellyfish-Derived Fungus Aspergillus flavus

Marine Drugs ◽  
2021 ◽  
Vol 19 (8) ◽  
pp. 417
Author(s):  
Dan-dan Li ◽  
Ying Wang ◽  
Eun La Kim ◽  
Jongki Hong ◽  
Jee H. Jung
Keyword(s):  
Aspergillus Flavus ◽  
Neuroprotective Effect ◽  
Neuroblastoma Cells ◽  
Neuroprotective Activity ◽  
Peroxisome Proliferator ◽  
Human Neuroblastoma ◽  
Peroxisome Proliferator Activated Receptor ◽  
Lactate Dehydrogenase Release ◽  
Ppar Γ ◽  
Induced Apoptosis

Peroxisome proliferator-activated receptor (PPAR) expression has been implicated in pathological states such as cancer, inflammation, diabetes, and neurodegeneration. We isolated natural PPAR agonists—eight 2,5-diketopiperazines—from the jellyfish-derived fungus Aspergillus flavus. Cyclo-(L-Pro-L-Phe) was the most potent PPAR-γ activator among the eight 2,5-DKPs identified. Cyclo-(L-Pro-L-Phe) activated PPAR-γ in Ac2F rat liver cells and SH-SY5Y human neuroblastoma cells. The neuroprotective effect of this partial PPAR-γ agonist was examined using the 3-(4, 5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, lactate dehydrogenase release, and the Hoechst 33342 staining assay in SH-SY5Y cells. Our findings revealed that cyclo-(L-Pro-L-Phe) reduced hydrogen peroxide-induced apoptosis as well as the generation of reactive oxygen species. Rhodamine 123 staining and western blotting revealed that cyclo-(L-Pro-L-Phe) prevented the loss of mitochondrial membrane potential and inhibited the activation of mitochondria-related apoptotic proteins, such as caspase 3 and poly (ADP-ribose) polymerase. Moreover, cyclo-(L-Pro-L-Phe) inhibited the activation and translocation of nuclear factor-kappa B. Thus, the partial PPAR-γ agonist cyclo-(L-Pro-L-Phe) demonstrated potential neuroprotective activity against oxidative stress-induced neurodegeneration in SH-SY5Y cells.

scholarly journals Protective Activity of Esculetin Against 3-Nitropropionic Acid Induced Neurotoxicity Via Scavenging Reactive Oxygen Species in Male Wistar Rats

2017 ◽  
Vol 9 (5) ◽  
Author(s):  
Arpita Karandikar ◽  
Sumathi Thangarajan
Keyword(s):  
Oxidative Stress ◽  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Neurodegenerative Disorder ◽  
Neuroprotective Effect ◽  
Neuroprotective Activity ◽  
Protein Carbonyls ◽  
Rat Striatum ◽  
Nitropropionic Acid ◽  
3 Nitropropionic Acid

Huntington’s disease (HD) is a devastating neurodegenerative disorder with no cure till date. Many genetic or chemically induced models have been developed in rodents to study the disease. 3-Nitropropionic (3-NP) acid is a well-known neurotoxin to induce Huntington’s disease (HD) in rodents. It replicates the pathology of HD by causing oxidative stress. Esculetin is a natural compound, a coumarin, known to have neuroprotective effect in a mouse model of Parkinson’s disease. In the present study, the neuroprotective effect of esculetin on 3-NP induced oxidative stress in rat striatum was determined by behavioral and biochemical parameters. Rats were induced with 3-NP (10mg/kg) intraperitoneally for 14 days and rats induced with 3-NP were treated with esculetin (25mg/kg and 50mg/kg) for 14 days. Esculetin attenuated the behaviour of rats in morris water maze, open field, forced swim, narrow beam walk and grip strength test. Biochemical effect of esculetin was also studied on oxidative stress markers, SDH and acetylcholinesterase. Esculetin treatment alleviated the increased values of acetylcholinesterase, protein carbonyls and lipid peroxidation. On treatment with esculetin, we observed that the levels of SOD, GSH, catalase, glutathione peroxidase, SDH were increased. The present study shows that the antioxidant activity of esculetin may be responsible for its neuroprotective activity against 3- nitropropionic acid induced neurotoxicity in rats

scholarly journals Neuroprotective Activity of Mentha Species on Hydrogen Peroxide-Induced Apoptosis in SH-SY5Y Cells

2020 ◽  
Author(s):  
Doaa M. Hanafy ◽  
Paul D. Prenzler ◽  
Geoffrey E. Burrows ◽  
Saliya Gurusinghe ◽  
Bashar Thejer ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Neurodegenerative Disorder ◽  
Cell Model ◽  
Neuronal Cell ◽  
Neuroprotective Activity ◽  
Caspase Activity ◽  
Neuroprotective Effects ◽  
Jnk Pathway ◽  
Apoptotic Protein

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder that develops as a consequence of different factors such as oxidative stress and accumulation of the protein amyloid β (Aβ) in the brain, resulting in apoptosis of neuronal cells. The search for a treatment for this disorder is essential as current medications are limited to alleviating symptoms and palliative effects. The aim of this study is to investigate the effects of mint extracts on selected mechanisms implicated in the development of AD. To enable a thorough investigation of mechanisms, including effects on -secretase (the enzyme the leads to the formation of A), on Aβ aggregation, and on oxidative stress and apoptosis pathways, a neuronal cell model, SH-SY5Y cells was selected. Six Mentha taxa were investigated for their in vitro β-secretase (BACE) and Aβ-aggregation inhibition activities. Also, their neuroprotective effects on H2O2-induced oxidative stress and apoptosis in SH-SY5Y cells were evaluated through caspase activity. Real-time PCR and Western blot analysis were carried out for the two most promising extracts to determine their effects on signalling pathways in SH-SY5Y cells. All mint extracts had strong BACE inhibition activity. M. requienii extracts showed excellent inhibition of Aβ-aggregation, while other extracts showed moderate inhibition. M. diemenica and M. requienii extracts lowered caspase activity. Exposure of SH-SY5Y cells to M. diemenica extracts resulted in a decrease in the expression of pro-apoptotic protein, Bax, and an elevation in the anti-apoptotic protein, Bcl-xL, potentially mediated by down-regulation of ASK1-JNK pathway. These results indicate that mint extracts could prevent the formation of Aβ and also could prevent their aggregation if they had already formed. M. diemenica and M. requienii extracts have potential to suppress apoptosis at the cellular level. Hence, mint extracts could provide a source of efficacious compounds for a therapeutic approach for AD.

scholarly journals Neuroprotective Properties of Kempferol Derivatives from Maesa membranacea against Oxidative Stress-Induced Cell Damage: An Association with Cathepsin D Inhibition and PI3K/Akt Activation

2021 ◽  
Vol 22 (19) ◽  
pp. 10363
Author(s):  
Danuta Jantas ◽  
Janusz Malarz ◽  
Thanh Nguyen Le ◽  
Anna Stojakowska
Keyword(s):  
Cathepsin D ◽  
Cell Damage ◽  
Neuroprotective Effect ◽  
Radical Scavenging ◽  
Neuroblastoma Cells ◽  
Neuroprotective Activity ◽  
Major Constituent ◽  
Neuroprotective Effects ◽  
Potential Health

As components of the human diet with potential health benefits, flavonols are the subject of numerous studies, confirming their antioxidant, free radical scavenging and anti-inflammatory activity. Taking into consideration the postulated pathogenesis of certain CNS dysfunctions characterized by neuronal degradation, flavonols may prevent the decay of neurons in multiple pathways. Leaves of Maesa membranacea yielded several flavonol glycosides including α-rhamnoisorobin (kaempferol 7-O-α-rhamnoside) and kaempferitrin (kaempferol 3,7-di-O-α-rhamnoside). The latter compound was a major constituent of the investigated plant material. Neuroprotective effects of kaempferitrin and α-rhamnoisorobin were tested in vitro using H2O2-, 6-OHDA- and doxorubicin-induced models of SH-SY5Y cell damage. Both undifferentiated and differentiated neuroblastoma cells were used in the experiments. α-Rhamnoisorobin at a concentration range of 1–10 µM demonstrated cytoprotective effects against H2O2-induced cell damage. The compound (at 1–10 µM) was also effective in attenuating 6-OHDA-induced neurotoxicity. In both H2O2- and 6-OHDA-induced cell damage, kaempferitrin, similar to isoquercitrin, demonstrated neuroprotective activity at the highest of the tested concentrations (50 µM). The tested flavonols were not effective in counteracting doxorubicin-induced cytotoxicity. Their caspase-3- and cathepsin D-inhibitory activities appeared to be structure dependent. Inhibition of the PI3-K/Akt pathway abolished the neuroprotective effect of the investigated flavonols.

scholarly journals Neuroprotective Activity of Mentha Species on Hydrogen Peroxide-Induced Apoptosis in SH-SY5Y Cells

Nutrients ◽  
2020 ◽  
Vol 12 (5) ◽  
pp. 1366 ◽  
Author(s):  
Doaa M. Hanafy ◽  
Paul D. Prenzler ◽  
Geoffrey E. Burrows ◽  
Saliya Gurusinghe ◽  
Bashar M. Thejer ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Neurodegenerative Disorder ◽  
Neuronal Damage ◽  
Cell Model ◽  
Amyloid Β ◽  
Neuronal Cell ◽  
Neuroprotective Activity ◽  
Caspase Activity ◽  
Apoptotic Protein ◽  
Aβ Aggregation

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder with an unclear cause. It appears that multiple factors participate in the process of neuronal damage including oxidative stress and accumulation of the protein amyloid β (Aβ) in the brain. The search for a treatment for this disorder is essential as current medications are limited to alleviating symptoms and palliative effects. The aim of this study is to investigate the effects of mint extracts on selected mechanisms implicated in the development of AD. To enable a thorough investigation of mechanisms, including effects on β-secretase (the enzyme that leads to the formation of Aβ), on Aβ aggregation, and on oxidative stress and apoptosis pathways, a neuronal cell model, SH-SY5Y cells, was selected. Six Mentha taxa were investigated for their in vitro β-secretase (BACE) and Aβ-aggregation inhibition activities. Moreover, their neuroprotective effects on H2O2-induced oxidative stress and apoptosis in SH-SY5Y cells were evaluated through caspase activity. Real-time PCR and Western blot analysis were carried out for the two most promising extracts to determine their effects on signalling pathways in SH-SY5Y cells. All mint extracts had strong BACE inhibition activity. M. requienii extracts showed excellent inhibition of Aβ-aggregation, while other extracts showed moderate inhibition. M. diemenica and M. requienii extracts lowered caspase activity. Exposure of SH-SY5Y cells to M. diemenica extracts resulted in a decrease in the expression of pro-apoptotic protein, Bax, and an elevation in the anti-apoptotic protein, Bcl-xL, potentially mediated by down-regulation of the ASK1-JNK pathway. These results indicate that mint extracts could prevent the formation of Aβ and also could prevent their aggregation if they had already formed. M. diemenica and M. requienii extracts have potential to suppress apoptosis at the cellular level. Hence, mint extracts could provide a source of efficacious compounds for a therapeutic approach for AD.

Sign in / Sign up

Export Citation Format

Share Document