Oxidative Stress, Mitochondrial Abnormalities and Proteins Deposition: Multitarget Approaches in Alzheimer's Disease

Nesi, Giulia; Sestito, Simona; Digiacomo, Maria; Rapposelli, Simona

doi:10.2174/1568026617666170607114232

Cited by 43 publications

(24 citation statements)

References 147 publications

(145 reference statements)

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“…Cell pretreatment with H 2 O 2 is known to cause the excessive release of ROS, which initiates DNA and mitochondrial damage, resulting in cell apoptosis (Dai et al, 2014;Ding et al, 2016;Fu et al, 2016). Accumulating evidence has shown that ROS production is associated with oxidative stress and mitochondrial anomalies (Nesi et al, 2017;Sundqvist et al, 2017;Franco-Iborra et al, 2018). We found that a-cyperone reduced the production of ROS in H 2 O 2 -treated SH-SY5Y cells.…”

Section: A B C D Ementioning

confidence: 62%

α-Cyperone Attenuates H2O2-Induced Oxidative Stress and Apoptosis in SH-SY5Y Cells via Activation of Nrf2

Huang

Liu

et al. 2020

Front. Pharmacol.

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a-Cyperone, extracted from Cyperus rotundus, has been reported to inhibit microgliamediated neuroinflammation. Oxidative stress and apoptosis play crucial roles in the course of Parkinson's disease (PD). PD is a common neurodegenerative disease characterized by selective death of dopaminergic neurons. This study was designed to investigate the neuroprotective effects of a-cyperone against hydrogen peroxide (H 2 O 2)induced oxidative stress and apoptosis in dopaminergic neuronal SH-SY5Y cells. Neurotoxicity was assessed by MTT assay and the measurement of lactic dehydrogenase (LDH) release. The level of reactive oxygen species (ROS) was measured by dichlorodihydrofluorescin diacetate (DCFH-DA) staining. The apoptosis of SH-SY5Y cells was evaluated by annexin-V-FITC staining. The translocation of NF-E2related factor 2 (Nrf2) was determined by western blot and immunofluorescence staining. Western blot analysis was conducted to determine the expression level of cleavedcaspase-3, the pro-apoptotic factor Bax, and the anti-apoptotic factor, Bcl-2. The results showed that a-cyperone substantially decreased H 2 O 2-induced death, release of LDH, and the production of ROS in SH-SY5Y cells. In addition, we found that a-cyperone attenuated H 2 O 2-induced cellular apoptosis. Moreover, a-cyperone remarkably reduced the expression of cleaved-caspase-3 and Bax, and upregulated Bcl-2. Furthermore, acyperone enhanced the nuclear translocation of Nrf2. Pretreatment with brusatol (BT, an Nrf2 inhibitor) attenuated a-cyperone-mediated suppression of ROS, cleaved-caspase-3, and Bax, as well as a-cyperone-induced Bcl-2 upregulation in H 2 O 2-treated SH-SY5Y cells. a-cyperone neuroprotection required Nrf2 activation. In conclusion, a-cyperone attenuated H 2 O 2-induced oxidative stress and apoptosis in SH-SY5Y cells via the activation of Nrf2, suggesting the potential of this compound in the prevention and treatment of PD.

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Section: A B C D Ementioning

confidence: 62%

α-Cyperone Attenuates H2O2-Induced Oxidative Stress and Apoptosis in SH-SY5Y Cells via Activation of Nrf2

Huang

Liu

et al. 2020

Front. Pharmacol.

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“…Notably, neurodegenerative diseases are multifactorial debilitating disorders involving multiple pathways that, in addition to protein misfolding and aggregation, are characterized by several metabolic changes, such as mitochondrial dysfunction, oxidative stress, and phosphorylation impairment, all occurring concurrently ( Nesi et al, 2017 ). Because of these multifactorial aspects and complexity, multi-target directed ligand (MTDL) design and discovery has emerged as a possible strategy for the treatment of neurodegenerative disorders ( Saba Sheikh et al, 2013 ).…”

Section: Discussionmentioning

confidence: 99%

New Insights into the Potential Roles of 3-Iodothyronamine (T1AM) and Newly Developed Thyronamine-Like TAAR1 Agonists in Neuroprotection

et al. 2017

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3-Iodothyronamine (T1AM) is an endogenous high-affinity ligand of the trace amine-associated receptor 1 (TAAR1), detected in mammals in many organs, including the brain. Recent evidence indicates that pharmacological TAAR1 activation may offer a novel therapeutic option for the treatment of a wide range of neuropsychiatric and metabolic disorders. To assess potential neuroprotection by TAAR1 agonists, in the present work, we initially investigated whether T1AM and its corresponding 3-methylbiaryl-methane analog SG-2 can improve learning and memory when systemically administered to mice at submicromolar doses, and whether these effects are modified under conditions of MAO inhibition by clorgyline. Our results revealed that when i.p. injected to mice, both T1AM and SG-2 produced memory-enhancing and hyperalgesic effects, while increasing ERK1/2 phosphorylation and expression of transcription factor c-fos. Notably, both compounds appeared to rely on the action of ubiquitous enzymes MAO to produce the corresponding oxidative metabolites that were then able to activate the histaminergic system. Since autophagy is key for neuronal plasticity, in a second line of experiments we explored whether T1AM and synthetic TAAR1 agonists SG1 and SG2 were able to induce autophagy in human glioblastoma cell lines (U-87MG). After treatment of U-87MG cells with 1 μM T1AM, SG-1, SG-2 transmission electron microscopy (TEM) and immunofluorescence (IF) showed a significant time-dependent increase of autophagy vacuoles and microtubule-associated protein 1 light chain 3 (LC3). Consistently, Western blot analysis revealed a significant increase of the LC3II/LC3I ratio, with T1AM and SG-1 being the most effective agents. A decreased level of the p62 protein was also observed after treatment with T1AM and SG-1, which confirms the efficacy of these compounds as autophagy inducers in U-87MG cells. In the process to dissect which pathway induces ATG, the effects of these compounds were evaluated on the PI3K-AKT-mTOR pathway. We found that 1 μM T1AM, SG-1 and SG-2 decreased pAKT/AKT ratio at 0.5 and 4 h after treatment, suggesting that autophagy is induced by inhibiting mTOR phosphorylation by PI3K-AKT-mTOR pathway. In conclusion, our study shows that T1AM and thyronamine-like derivatives SG-1 and SG-2 might represent valuable tools to therapeutically intervene with neurological disorders.

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“…Furthermore, Haber Weiss and Fenton reactions are involved in several cellular redox processes, but in vivo evidences have shown that Aβ neurotoxicity is dependent on the catalytic generation of H 2 O 2 and hydroxyl radical (OH) which are enhanced by the presence of Fe +2 /Fe 3+ , Aβ-Cu +2 and Aβ-Zn 2+ complexes [ 28 - 32 ]. Mitochondria are the major intracellular targets of soluble Aβ oligomers (sAβ) that in excess, could interfere in the integrity of the mitochondrial membrane and in its functionality, causing overproduction of OS, inhibition of cellular respiration and ATP production [ 33 - 35 ]. Enough data support that sAβ interfere in mitochondria by a result of changes in the homeostasis of intracellular Ca 2+ signaling, causing ion massive influx in mitochondria and neuronal apoptosis [ 33 ].…”

Section: Introductionmentioning

confidence: 99%

“…Enough data support that sAβ interfere in mitochondria by a result of changes in the homeostasis of intracellular Ca 2+ signaling, causing ion massive influx in mitochondria and neuronal apoptosis [ 33 ]. The increase in the concentration of Ca 2+ in mitochondria causes the opening of the mitochondrial permeability transition pore (MPTP), allowing the uncontrolled bidirectional passage of large molecules, resulting in disintegration of organelles and functional structure [ 34 , 35 ]. The associative effect of all these pathophysiological changes, including protein fragments deposition (Aβ and tau), coupled with the uncontrolled production of radical species, are crucial for the installation and progression of a complex neuroinflammatory process [ 36 - 40 ].…”

Section: Introductionmentioning

confidence: 99%

Molecular Hybridization as a Tool in the Design of Multi-target Directed Drug Candidates for Neurodegenerative Diseases

Gontijo

Viegas

Ortiz

et al. 2020

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Neurodegenerative Diseases (NDs) are progressive multifactorial neurological pathologies related to neuronal impairment and functional loss from different brain regions. Currently, no effective treatments are available for any NDs, and this lack of efficacy has been attributed to the multitude of interconnected factors involved in their pathophysiology. In the last two decades, a new approach for the rational design of new drug candidates, also called multitarget-directed ligands (MTDLs) strategy, has emerged and has been used in the design and for the development of a variety of hybrid compounds capable to act simultaneously in diverse biological targets. Based on the polypharmacology concept, this new paradigm has been thought as a more secure and effective way for modulating concomitantly two or more biochemical pathways responsible for the onset and progress of NDs, trying to overcome low therapeutical effectiveness. As a complement to our previous review article (Curr. Med. Chem. 2007, 14 (17), 1829-1852. https://doi.org/10.2174/092986707781058805), herein we aimed to cover the period from 2008 to 2019 and highlight the most recent advances of the exploitation of Molecular Hybridization (MH) as a tool in the rational design of innovative multifunctional drug candidate prototypes for the treatment of NDs, specially focused on AD, PD, HD and ALS.

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Oxidative Stress, Mitochondrial Abnormalities and Proteins Deposition: Multitarget Approaches in Alzheimer's Disease

Cited by 43 publications

References 147 publications

α-Cyperone Attenuates H2O2-Induced Oxidative Stress and Apoptosis in SH-SY5Y Cells via Activation of Nrf2

α-Cyperone Attenuates H2O2-Induced Oxidative Stress and Apoptosis in SH-SY5Y Cells via Activation of Nrf2

New Insights into the Potential Roles of 3-Iodothyronamine (T1AM) and Newly Developed Thyronamine-Like TAAR1 Agonists in Neuroprotection

Molecular Hybridization as a Tool in the Design of Multi-target Directed Drug Candidates for Neurodegenerative Diseases

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