scholarly journals N-Acetylcysteine Nanocarriers Protect against Oxidative Stress in a Cellular Model of Parkinson’s Disease

Antioxidants ◽  
2020 ◽  
Vol 9 (7) ◽  
pp. 600 ◽  
Author(s):  
Leah Mursaleen ◽  
Brendon Noble ◽  
Stefanie Ho Yi Chan ◽  
Satyanarayana Somavarapu ◽  
Mohammed Gulrez Zariwala
Keyword(s):  
Oxidative Stress ◽  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Cell Viability ◽  
Iron Status ◽  
Thiobarbituric Acid ◽  
Iron Chelator ◽  
Disease Modifying Therapy ◽  
First Time ◽  
The Brain

Oxidative stress is a key mediator in the development and progression of Parkinson’s disease (PD). The antioxidant N-acetylcysteine (NAC) has generated interest as a disease-modifying therapy for PD but is limited due to poor bioavailability, a short half-life, and limited access to the brain. The aim of this study was to formulate and utilise mitochondria-targeted nanocarriers for delivery of NAC alone and in combination with the iron chelator deferoxamine (DFO), and assess their ability to protect against oxidative stress in a cellular rotenone PD model. Pluronic F68 (P68) and dequalinium (DQA) nanocarriers were prepared by a modified thin-film hydration method. An MTT assay assessed cell viability and iron status was measured using a ferrozine assay and ferritin immunoassay. For oxidative stress, a modified cellular antioxidant activity assay and the thiobarbituric acid-reactive substances assay and mitochondrial hydroxyl assay were utilised. Overall, this study demonstrates, for the first time, successful formulation of NAC and NAC + DFO into P68 + DQA nanocarriers for neuronal delivery. The results indicate that NAC and NAC + DFO nanocarriers have the potential characteristics to access the brain and that 1000 μM P68 + DQA NAC exhibited the strongest ability to protect against reduced cell viability (p = 0.0001), increased iron (p = 0.0033) and oxidative stress (p ≤ 0.0003). These NAC nanocarriers therefore demonstrate significant potential to be transitioned for further preclinical testing for PD.

scholarly journals Hesperetin protects SH-SY5Y cells against 6- hydroxydopamine-induced neurotoxicity via activation of NRF2/ARE signaling pathways

2020 ◽  
Vol 19 (6) ◽  
pp. 1197-1201 ◽  
Author(s):  
Jing Li ◽  
Yue Liu ◽  
Li Wang ◽  
Zhaowei Gu ◽  
Zhigang Huan ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Cell Viability ◽  
Heme Oxygenase 1 ◽  
Protective Effects ◽  
Neuroprotective Effects ◽  
Ldh Release ◽  
6 Hydroxydopamine

Purpose: To investigation the protective effects of hesperetin against 6-hydroxydopamine (6-OHDA)- induced neurotoxicity. Methods: SH-SY5Y cells were incubated with 6-OHDA to create an in vitro model of neurotoxicity. This model was used to test the neuroprotective effects of hesperetin. Cell viability was assessed by MTT and lactate dehydrogenase (LDH) release assays. Flow cytometry and western blot were used to quantify apoptosis. Oxidative stress was evaluated by determining intracellular glutathione (GSH), malondialdehyde (MDA), superoxide dismutase (SOD), and reactive oxygen species (ROS). Results: In SH-SY5Y cells, treatment with 6-OHDA decreased cell viability and promoted LDH release. However, exogenous hesperetin protected against 6-OHDA-mediated toxicity. Similarly, although incubation with 6-OHDA induced apoptosis and increased cleaved caspase-3 and -9 levels, treatment with hesperetin protected against these effects. Treatment with 6-OHDA also led to significant oxidative stress, as indicated by reduced GSH and SOD levels and increased MDA and ROS levels in SH-SY5Y cells. However, these changes were reversed by pre-treatment with hesperetin. Of interest, hesperetin led to changes in 6-OHDA-induced expression of NRF2, heme oxygenase-1 (HO-1), glutamate-cysteine ligase (GCL) catalytic subunit (GCLC), and GCL modulatory (GCLM). Conclusion: Hesperetin protects against cell toxicity, apoptosis, and oxidative stress via activation of NRF2 pathway in a 6-OHDA-induced model of neurotoxicity. Future studies should investigate the use of hesperetin as a potential therapeutic approach for prevention or management of Parkinson’s disease. Keywords: Hesperetin, 6-OHDA, Neurotoxicity, NRF2, Parkinson’s disease

scholarly journals Systemic α-synuclein injection triggers selective neuronal pathology as seen in patients with Parkinson’s disease

2019 ◽  
Author(s):  
Wei-Li Kuan ◽  
Katherine Stott ◽  
Xiaoling He ◽  
Tobias C. Wood ◽  
Sujeong Yang ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Brain Regions ◽  
Neuronal Populations ◽  
Novel Approach ◽  
Quaternary Structures ◽  
Cellular Pathology ◽  
First Time ◽  
The Brain ◽  
Delivery Approach

AbstractParkinson’s disease (PD) is an α-synucleinopathy characterized by the progressive loss of specific neuronal populations. Here, we develop a novel approach to transvascularly deliver proteins of complex quaternary structures, including α-synuclein preformed fibrils (pff). We show that a single systemic administration of α-synuclein pff triggers pathological transformation of endogenous α-synuclein in non-transgenic rats, which leads to neurodegeneration in discrete brain regions. Specifically, pff-exposed animals displayed a progressive deterioration in gastrointestinal and olfactory functions, which corresponded with the presence of cellular pathology in the central and enteric nervous systems. The α-synuclein pathology generated was both time dependent and region specific. Interestingly, the most significant neuropathological changes were observed in those brain regions affected in the early stages of PD. Our data therefore demonstrate for the first time that a single, transvascular administration of α-synuclein pff can lead to selective regional neuropathology resembling the premotor stage of idiopathic PD. Furthermore, this novel delivery approach could also be used to deliver a range of other pathogenic, as well as therapeutic, protein cargos transvascularly to the brain.

scholarly journals Accumulation of alpha-synuclein within the liver, potential role in the clearance of brain pathology associated with Parkinson’s disease

2021 ◽  
Vol 9 (1) ◽  
Author(s):  
Juan F. Reyes ◽  
Sara Ekmark-Léwen ◽  
Marina Perdiki ◽  
Therése Klingstedt ◽  
Alana Hoffmann ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Potential Role ◽  
Alpha Synuclein ◽  
Wild Type ◽  
Junction Protein ◽  
The Central Nervous System ◽  
Gap Junction Protein ◽  
First Time ◽  
The Brain

AbstractAlpha-synuclein (α-syn) aggregation is the hallmark pathological lesion in brains of patients with Parkinson’s disease (PD) and related neurological disorders characterized as synucleinopathies. Accumulating evidence now indicates that α-syn deposition is also present within the gut and other peripheral organs outside the central nervous system (CNS). In the current study, we demonstrate for the first time that α-syn pathology also accumulates within the liver, the main organ responsible for substance clearance and detoxification. We further demonstrate that cultured human hepatocytes readily internalize oligomeric α-syn assemblies mediated, at least in part, by the gap junction protein connexin-32 (Cx32). Moreover, we identified a time-dependent accumulation of α-syn within the liver of three different transgenic (tg) mouse models expressing human α-syn under CNS-specific promoters, despite the lack of α-syn mRNA expression within the liver. Such a brain-to-liver transmission route could be further corroborated by detection of α-syn pathology within the liver of wild type mice one month after a single striatal α-syn injection. In contrast to the synucleinopathy models, aged mice modeling AD rarely show any amyloid-beta (Aß) deposition within the liver. In human post-mortem liver tissue, we identified cases with neuropathologically confirmed α-syn pathology containing α-syn within hepatocellular structures to a higher degree (75%) than control subjects without α-syn accumulation in the brain (57%). Our results reveal that α-syn accumulates within the liver and may be derived from the brain or other peripheral sources. Collectively, our findings indicate that the liver may play a role in the clearance and detoxification of pathological proteins in PD and related synucleinopathies.

scholarly journals Astragaloside IV Protects 6-Hydroxydopamine-Induced SH-SY5Y Cell Model of Parkinson’s Disease via Activating the JAK2/STAT3 Pathway

2021 ◽  
Vol 15 ◽  
Author(s):  
ZhengHu Xu ◽  
Dongfeng Yang ◽  
Xiaojing Huang ◽  
Huai Huang
Keyword(s):  
Oxidative Stress ◽  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Cell Viability ◽  
Cell Model ◽  
Astragaloside Iv ◽  
Stat3 Pathway ◽  
Apoptosis Rate ◽  
6 Hydroxydopamine ◽  
And Oxidative Stress

ObjectivesAstragaloside IV (AS-IV), the main active component of Astragalus membranaceus, bears anti-inflammatory, antioxidant, and neuroprotective activity. Parkinson’s disease (PD) is a common neurodegenerative disease. This study explored the protective effect of AS-IV on the cell model of PD.Materials and MethodsSH-SY5Y cells were incubated with different concentrations (10, 50, 100, 150, and 200 μM) of 6-hydroxydopamine (6-OHDA) for 0, 3, 6, 12, 24, and 48 h to establish the PD cell model. Different concentrations (0, 25, 50, 100, 150, and 200 μM) of AS-IV or 15 mM JAK2/STAT3 pathway inhibitor SC99 was added for intervention 2 h before 6-OHDA treatment. The viability and morphological damage of 6-OHDA-treated SH-SY5Y cells were measured using MTT assay and Hoechst 33258 staining. The expression of microtubule associated protein 2 (MAP2) was detected by immunofluorescence staining. The levels of inflammation and oxidative stress were measured using ELISA. Apoptosis of 6-OHDA-treated SH-SY5Y cells was detected using flow cytometry, and phosphorylation level of JAK2 and STAT3 were detected using Western blot analysis.ResultsThe survival rate of SH-SY5Y cells treated with 100 μM 6-OHDA for 24 h was about 50%. AS-IV (25–100 μM) significantly improved the viability (all p < 0.01), increased MAP2 expression, and repaired the morphological damage induced by 6-OHDA. AS-IV inhibited IL-1β, IL-6, and TNF-α level (all p < 0.05), reduced MDA and ROS content and increased SOD concentration, thereby reducing inflammation and oxidative stress (all p < 0.01) in 6-OHDA-treated SH-SY5Y cells. Moreover, AS-IV decreased apoptosis rate and Bax/Bcl-2 ratio induced by 6-OHDA (all p < 0.05). Mechanically, AS-IV significantly increased the phosphorylation of JAK2 and STAT3 (p < 0.01); the addition of SC99 decreased the cell viability, increased the apoptosis rate, enhanced the levels of inflammatory factors and oxidative stress.ConclusionAS-IV enhanced the cell viability, and inhibited apoptosis, inflammation and oxidative stress of 6-OHDA-treated SH-SY5Y cells via activating the JAK2/STAT3 signaling pathway. This study may confer novel insights for the management of PD.

scholarly journals Synthesis of Alginate-Curcumin Nanocomposite and Its Protective Role in Transgenic Drosophila Model of Parkinson’s Disease

2013 ◽  
Vol 2013 ◽  
pp. 1-8 ◽  
Author(s):  
Yasir Hasan Siddique ◽  
Wasi Khan ◽  
Braj Raj Singh ◽  
Alim H. Naqvi
Keyword(s):  
Oxidative Stress ◽  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Lewy Bodies ◽  
Protective Role ◽  
Alpha Synuclein ◽  
Lower Permeability ◽  
Normal Human ◽  
Climbing Ability ◽  
The Brain

The genetic models in Drosophila provide a platform to understand the mechanism associated with degenerative diseases. The model for Parkinson's disease (PD) based on normal human alpha-synuclein (αS) expression was used in the present study. The aggregation of αS in brain leads to the formation of Lewy bodies and selective loss of dopaminergic neurons due to oxidative stress. Polyphenols generally have the reduced oral bioavailability, increased metabolic turnover, and lower permeability through the blood brain barrier. In the present study, the effect of synthesized alginate-curcumin nanocomposite was studied on the climbing ability of the PD model flies, lipid peroxidation, and apoptosis in the brain of PD model flies. The alginate-curcumin nanocomposite at final doses of 10−5, 10−3, and 10−1 g/mL was supplemented with diet, and the flies were allowed to feed for 24 days. A significant dose-dependent delay in the loss of climbing ability and reduction in the oxidative stress and apoptosis in the brain of PD model flies were observed. The results suggest that alginate-curcumin nanocomposite is potent in delaying the climbing disability of PD model flies and also reduced the oxidative stress as well as apoptosis in the brain of PD model flies.

scholarly journals Symmetric and Asymmetric Synapses Driving Neurodegenerative Disorders

Symmetry ◽  
2021 ◽  
Vol 13 (12) ◽  
pp. 2333
Author(s):  
Daniel Romaus-Sanjurjo ◽  
Antía Custodia ◽  
Marta Aramburu-Núñez ◽  
Adrián Posado-Fernández ◽  
Laura Vázquez-Vázquez ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Dopaminergic Neurons ◽  
Tau Proteins ◽  
Midbrain Dopaminergic Neurons ◽  
Different Types ◽  
The Central Nervous System ◽  
First Time ◽  
The Brain

In 1959, E. G. Gray described two different types of synapses in the brain for the first time: symmetric and asymmetric. Later on, symmetric synapses were associated with inhibitory terminals, and asymmetric synapses to excitatory signaling. The balance between these two systems is critical to maintain a correct brain function. Likewise, the modulation of both types of synapses is also important to maintain a healthy equilibrium. Cerebral circuitry responds differently depending on the type of damage and the timeline of the injury. For example, promoting symmetric signaling following ischemic damage is beneficial only during the acute phase; afterwards, it further increases the initial damage. Synapses can be also altered by players not directly related to them; the chronic and long-term neurodegeneration mediated by tau proteins primarily targets asymmetric synapses by decreasing neuronal plasticity and functionality. Dopamine represents the main modulating system within the central nervous system. Indeed, the death of midbrain dopaminergic neurons impairs locomotion, underlying the devastating Parkinson’s disease. Herein, we will review studies on symmetric and asymmetric synapses plasticity after three different stressors: symmetric signaling under acute damage—ischemic stroke; asymmetric signaling under chronic and long-term neurodegeneration—Alzheimer’s disease; symmetric and asymmetric synapses without modulation—Parkinson’s disease.

scholarly journals Effect of Nebivolol on MPTP Induced Parkinson’s Disease in Mice

2021 ◽  
Vol 69 (1) ◽  
Author(s):  
Karthigadevi. K ◽  
Anbazhagan. S ◽  
Jajjara Gopi Sudheer Kumar ◽  
Kavimani. S
Keyword(s):  
Oxidative Stress ◽  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Parkinson Disease ◽  
Dopaminergic Neurons ◽  
Neurodegenerative Disorder ◽  
Blocking Agent ◽  
Protective Effects ◽  
The Brain ◽  
Anti Inflammation

Parkinson’s disease is the major neurodegenerative disorder, which is due to the loss of dopaminergic neurons in the brain and results in bradykinesia, rigidity, tremor and instable posture. Oxidative stress, Inflammation, Apoptosis has been implicated in the molecular etiopathogenesis of Parkinson disease. In the present study, Nebivolol, a Cardioselective ?-blocking agent which is also reported as an antioxidant, anti-inflammation, anticonvulsant, inhibition of apoptosis and protective effects on gastric ulcer. Hence, nebivolol has been tested for its antiparkinson activity against 1-Methyl, 4-Phenyl-1,2,3,6-Tetrahydropyridine (MPTP) induced model of Parkinson disease in mice. From this study, the result shown that the nebivolol exerts its beneficial effect against MPTP induced Parkinson’s disease by virtue of its antioxidative, anti-inflammatory and by increases the Dopamine levels in the brain.

scholarly journals Minireview on the Relations between Gut Microflora and Parkinson’s Disease: Further Biochemical (Oxidative Stress), Inflammatory, and Neurological Particularities

2020 ◽  
Vol 2020 ◽  
pp. 1-15 ◽  
Author(s):  
Ovidiu-Dumitru Ilie ◽  
Alin Ciobica ◽  
Jack McKenna ◽  
Bogdan Doroftei ◽  
Ioannis Mavroudis
Keyword(s):  
Oxidative Stress ◽  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Gastrointestinal Tract ◽  
Gastrointestinal Symptoms ◽  
Progressive Increase ◽  
Signalling Pathways ◽  
Gut Microflora ◽  
Number Of Patients ◽  
The Brain

The aetiology of Parkinson’s disease (PD) is a highly debated topic. Despite the progressive increase in the number of patients diagnosed with PD over the last couple of decades, the causes remain largely unknown. This report is aimed at highlighting the main features of the microbial communities which have been termed “the second brain” that may be a major participant in the etiopathophysiology of PD. It is possible that dysbiosis could be caused by an overactivity of proinflammatory cytokines which act on the gastrointestinal tract as well as infections. The majority of patients who are diagnosed with PD display gastrointestinal symptoms as one of the earliest features. In addition, an unbalanced cycle of oxidative stress caused by dysbacteriosis may have the effect of gradually promoting PD’s specific phenotype. Thus, it seems that bacteria possess the ability to manipulate the brain by initiating specific responses, defining their capability to configure the human body, with oxidative stress playing a pivotal role in preventing infections but also in activating related signalling pathways.

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