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17 pages, 3576 KiB

Open AccessArticle

O-Cyclic Phytosphingosine-1-Phosphate Protects against Motor Dysfunctions and Glial Cell Mediated Neuroinflammation in the Parkinson’s Disease Mouse Models

by Hyeon Jin Lee, Kyonghwan Choe, Jun Sung Park, Amjad Khan, Min Woo Kim, Tae Ju Park and Myeong Ok Kim

Antioxidants 2022, 11(11), 2107; https://doi.org/10.3390/antiox11112107 - 26 Oct 2022

Cited by 9 | Viewed by 2457

Abstract

O-cyclic phytosphingosine-1-phosphate (cPS1P) is a novel and chemically synthesized sphingosine metabolite derived from phytosphingosine-1-phosphate (S1P). This study was undertaken to unveil the potential neuroprotective effects of cPS1P on two different mouse models of Parkinson’s disease (PD). The study used 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and neuron [...] Read more.

O-cyclic phytosphingosine-1-phosphate (cPS1P) is a novel and chemically synthesized sphingosine metabolite derived from phytosphingosine-1-phosphate (S1P). This study was undertaken to unveil the potential neuroprotective effects of cPS1P on two different mouse models of Parkinson’s disease (PD). The study used 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and neuron specific enolase promoter human alpha-synuclein (NSE-hαSyn) Korl transgenic mice. MPTP was injected for five consecutive days and cPS1P was injected for alternate days for six weeks intraperitoneally. We performed behavioral tests and analyzed the immunohistochemistry and immunofluorescence staining in the substantia nigra pars compacta (SNpc) and the striatum. The behavior tests showed a significant reduction in the motor functions in the PD models, which was reversed with the administration of cPS1P. In addition, both PD-models showed reduced expression of the sphingosine-1-phosphate receptor 1 (S1PR1), and α-Syn which was restored with cPS1P treatment. In addition, administration of cPS1P restored dopamine-related proteins such as tyrosine hydroxylase (TH), vesicular monoamine transporter 2 (VMAT2), and dopamine transporter (DAT). Lastly, neuroinflammatory related markers such as glial fibrillary acidic protein (GFAP), ionized calcium-binding adapter protein-1 (Iba-1), c-Jun N-terminal kinases (JNK), nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kB), tumor necrosis factor-alpha (TNF-α), and interleukin 1 beta (IL-1β) were all reduced after cPS1P administration. The overall findings supported the notion that cPS1P protects against dopamine depletion, neuroinflammation, and PD-associated symptoms. Full article

(This article belongs to the Special Issue Oxidative Stress and Neuroinflammation in Neurological and Neurodegenerative Disorders)

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16 pages, 3592 KiB

Open AccessArticle

Folic Acid Improves Parkin-Null Drosophila Phenotypes and Transiently Reduces Vulnerable Dopaminergic Neuron Mitochondrial Hydrogen Peroxide Levels and Glutathione Redox Equilibrium

by Katherine L. Houlihan, Petros P. Keoseyan, Amber N. Juba, Tigran Margaryan, Max E. Voss, Alexander M. Babaoghli, Justin M. Norris, Greg J. Adrian, Artak Tovmasyan and Lori M. Buhlman

Antioxidants 2022, 11(10), 2068; https://doi.org/10.3390/antiox11102068 - 20 Oct 2022

Cited by 3 | Viewed by 2246

Abstract

Loss-of-function parkin mutations cause oxidative stress and degeneration of dopaminergic neurons in the substantia nigra. Several consequences of parkin mutations have been described; to what degree they contribute to selective neurodegeneration remains unclear. Specific factors initiating excessive reactive oxygen species production, inefficient antioxidant [...] Read more.

Loss-of-function parkin mutations cause oxidative stress and degeneration of dopaminergic neurons in the substantia nigra. Several consequences of parkin mutations have been described; to what degree they contribute to selective neurodegeneration remains unclear. Specific factors initiating excessive reactive oxygen species production, inefficient antioxidant capacity, or a combination are elusive. Identifying key oxidative stress contributors could inform targeted therapy. The absence of Drosophila parkin causes selective degeneration of a dopaminergic neuron cluster that is functionally homologous to the substantia nigra. By comparing observations in these to similar non-degenerating neurons, we may begin to understand mechanisms by which parkin loss of function causes selective degeneration. Using mitochondrially targeted redox-sensitive GFP2 fused with redox enzymes, we observed a sustained increased mitochondrial hydrogen peroxide levels in vulnerable dopaminergic neurons of parkin-null flies. Only transient increases in hydrogen peroxide were observed in similar but non-degenerating neurons. Glutathione redox equilibrium is preferentially dysregulated in vulnerable neuron mitochondria. To shed light on whether dysregulated glutathione redox equilibrium primarily contributes to oxidative stress, we supplemented food with folic acid, which can increase cysteine and glutathione levels. Folic acid improved survival, climbing, and transiently decreased hydrogen peroxide and glutathione redox equilibrium but did not mitigate whole-brain oxidative stress. Full article

(This article belongs to the Special Issue Oxidative Stress and Neuroinflammation in Neurological and Neurodegenerative Disorders)

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17 pages, 4101 KiB

Open AccessArticle

Assessing the Neurotoxicity of a Sub-Optimal Dose of Rotenone in Zebrafish (Danio rerio) and the Possible Neuroactive Potential of Valproic Acid, Combination of Levodopa and Carbidopa, and Lactic Acid Bacteria Strains

by Ovidiu-Dumitru Ilie, Raluca Duta, Ioana-Miruna Balmus, Alexandra Savuca, Adriana Petrovici, Ilinca-Bianca Nita, Lucian-Mihai Antoci, Roxana Jijie, Cosmin-Teodor Mihai, Alin Ciobica, Mircea Nicoara, Roxana Popescu, Romeo Dobrin, Carmen Solcan, Anca Trifan, Carol Stanciu and Bogdan Doroftei

Antioxidants 2022, 11(10), 2040; https://doi.org/10.3390/antiox11102040 - 17 Oct 2022

Cited by 5 | Viewed by 5721

Abstract

Parkinson’s disease (PD) is an enigmatic neurodegenerative disorder that is currently the subject of extensive research approaches aiming at deepening the understanding of its etiopathophysiology. Recent data suggest that distinct compounds used either as anticonvulsants or agents usually used as dopaminergic agonists or [...] Read more.

Parkinson’s disease (PD) is an enigmatic neurodegenerative disorder that is currently the subject of extensive research approaches aiming at deepening the understanding of its etiopathophysiology. Recent data suggest that distinct compounds used either as anticonvulsants or agents usually used as dopaminergic agonists or supplements consisting of live active lactic acid bacteria strains might alleviate and improve PD-related phenotypes. This is why we aimed to elucidate how the administration of rotenone (ROT) disrupts homeostasis and the possible neuroactive potential of valproic acid (VPA), antiparkinsonian agents (levodopa and carbidopa – LEV+CARB), and a mixture of six Lactobacillus and three Bifidobacterium species (PROBIO) might re-establish the optimal internal parameters. ROT causes significant changes in the central nervous system (CNS), notably reduced neurogenesis and angiogenesis, by triggering apoptosis, reflected by the increased expression of PARKIN and PINK1 gene(s), low brain dopamine (DA) levels, and as opposed to LRRK2 and SNCA compared with healthy zebrafish. VPA, LEV/CARB, and PROBIO sustain neurogenesis and angiogenesis, manifesting a neuroprotective role in diminishing the effect of ROT in zebrafish. Interestingly, none of the tested compounds influenced oxidative stress (OS), as reflected by the level of malondialdehyde (MDA) level and superoxide dismutase (SOD) enzymatic activity revealed in non-ROT-exposed zebrafish. Overall, the selected concentrations were enough to trigger particular behavioral patterns as reflected by our parameters of interest (swimming distance (mm), velocity (mm/s), and freezing episodes (s)), but sequential testing is mandatory to decipher whether they exert an inhibitory role following ROT exposure. In this way, we further offer data into how ROT may trigger a PD-related phenotype and the possible beneficial role of VPA, LEV+CARB, and PROBIO in re-establishing homeostasis in Danio rerio. Full article

(This article belongs to the Special Issue Oxidative Stress and Neuroinflammation in Neurological and Neurodegenerative Disorders)

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14 pages, 1006 KiB

Open AccessArticle

Myeloperoxidase and Advanced Oxidation Protein Products in the Cerebrospinal Fluid in Women and Men with Parkinson’s Disease

by Emilio Fernández-Espejo, Fernando Rodríguez de Fonseca, Ana Luisa Gavito, Antonio Córdoba-Fernández, José Chacón and Ángel Martín de Pablos

Antioxidants 2022, 11(6), 1088; https://doi.org/10.3390/antiox11061088 - 30 May 2022

Cited by 8 | Viewed by 2567

Abstract

Background: Myeloperoxidase (MPO) and advanced oxidation protein products, or AOPP (a type of MPO-derived chlorinated adducts), have been implicated in Parkinson´s disease (PD). Human MPO also show sex-based differences in PD. The objective was to study the relationship of MPO and AOPP in [...] Read more.

Background: Myeloperoxidase (MPO) and advanced oxidation protein products, or AOPP (a type of MPO-derived chlorinated adducts), have been implicated in Parkinson´s disease (PD). Human MPO also show sex-based differences in PD. The objective was to study the relationship of MPO and AOPP in the cerebrospinal fluid (CSF) with motor features of idiopathic PD in male and female patients. Methods: MPO concentration and activity and AOPP content were measured in the CSF and serum in 34 patients and 30 controls. CSF leukocytes and the integrity of the blood-brain barrier were evaluated. Correlations of MPO and AOPP with clinical variables were examined. Results: The blood-brain barrier was intact and CSF leukocyte count was normal in all patients. CSF MPO concentration and activity were similar in the cohort of patients and controls, but CSF MPO content was significantly higher in male patients than in PD women (p = 0.0084). CSF MPO concentration correlated with disease duration in male and female patients (p < 0.01). CSF MPO concentration was significantly higher in men with disease duration ≥12 years versus the remainder of the male subjects (p < 0.01). Changes in CSF MPO in women were not significant. Serum MPO concentration and activity were significantly higher in all PD patients relative to controls (p < 0.0001). CSF MPO was not correlated with serum MPO. Serum AOPP were detected in all patients, but CSF AOPP was undetectable in 53% of patients. AOPP were not quantifiable in controls. Conclusions: CSF MPO is not a good biomarker for PD because mean CSF MPO concentration and activity are not different between the cohort of patients and controls. CSF MPO concentration positively correlated with disease duration in men and women, but CSF MPO is significantly enhanced only in male patients with disease duration longer than 12 years. It can be hypothesized that the MPO-related immune response in early-stage PD might be weak in all patients, but then the MPO-related immune response is progressively enhanced in men, not women. Since the blood-brain barrier is intact, and CSF MPO is not correlated with serum MPO, CSF myeloperoxidase would reflect MPO content in brain cells, not blood-derived cells. Finally, serum AOPP was detected in all patients, but not controls, which is consistent with the occurrence of chlorinative stress in blood serum in PD. The study of CSF AOPP as biomarker could not be assessed because the ELISA assay was hampered by its detection limit in the CSF. Full article

(This article belongs to the Special Issue Oxidative Stress and Neuroinflammation in Neurological and Neurodegenerative Disorders)

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13 pages, 12148 KiB

Open AccessArticle

Cerebral Oxidative Stress in Early Alzheimer’s Disease Evaluated by ⁶⁴Cu-ATSM PET/MRI: A Preliminary Study

by Hidehiko Okazawa, Masamichi Ikawa, Tetsuya Tsujikawa, Tetsuya Mori, Akira Makino, Yasushi Kiyono, Yasunari Nakamoto, Hirotaka Kosaka and Makoto Yoneda

Antioxidants 2022, 11(5), 1022; https://doi.org/10.3390/antiox11051022 - 22 May 2022

Cited by 9 | Viewed by 2733

Abstract

Oxidative stress imaging using diacetyl-bis (N⁴-methylthiosemicarbazone) (Cu-ATSM) was applied to the evaluation of patients with early Alzheimer’s disease (eAD). Ten eAD patients (72 ± 9 years) and 10 age-matched healthy controls (HCs) (73 ± 9 years) participated in this study. [...] Read more.

Oxidative stress imaging using diacetyl-bis (N⁴-methylthiosemicarbazone) (Cu-ATSM) was applied to the evaluation of patients with early Alzheimer’s disease (eAD). Ten eAD patients (72 ± 9 years) and 10 age-matched healthy controls (HCs) (73 ± 9 years) participated in this study. They underwent dynamic PET/MRI using ¹¹C-PiB and ⁶⁴Cu-ATSM with multiple MRI sequences. To evaluate cerebral oxidative stress, three parameters of ⁶⁴Cu-ATSM PET were compared: standardized uptake value (SUV), tracer influx rate (K_in), and a rate constant k₃. The input functions were estimated by the image-derived input function method. The relative differences were analyzed by statistical parametric mapping (SPM) using SUV and K_in images. All eAD patients had positive and HC subjects had negative PiB accumulation, and MMSE scores were significantly different between them. The ⁶⁴Cu-ATSM accumulation tended to be higher in eAD than in HCs for both SUV and K_in. When comparing absolute values, eAD patients had a greater K_in in the posterior cingulate cortex and a greater k₃ in the hippocampus compared with lobar cortical values of HCs. In SPM analysis, eAD had an increased left operculum and decreased bilateral hippocampus and anterior cingulate cortex compared to HCs. ⁶⁴Cu-ATSM PET/MRI and tracer kinetic analysis elucidated cerebral oxidative stress in the eAD patients, particularly in the cingulate cortex and hippocampus. Full article

(This article belongs to the Special Issue Oxidative Stress and Neuroinflammation in Neurological and Neurodegenerative Disorders)

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16 pages, 1079 KiB

Open AccessArticle

A Pathway-Based Genetic Score for Oxidative Stress: An Indicator of Host Vulnerability to Phthalate-Associated Adverse Neurodevelopment

by Samuel Tanner, Sarah Thomson, Katherine Drummond, Martin O’Hely, Christos Symeonides, Toby Mansell, Richard Saffery, Peter D. Sly, Fiona Collier, David Burgner, Eva J. Sugeng, Terence Dwyer, Peter Vuillermin, Anne-Louise Ponsonby and on behalf of the Barwon Infant Study Investigator Group

Antioxidants 2022, 11(4), 659; https://doi.org/10.3390/antiox11040659 - 29 Mar 2022

Cited by 8 | Viewed by 4663

Abstract

The developing brain is highly sensitive to environmental disturbances, and adverse exposures can act through oxidative stress. Given that oxidative stress susceptibility is determined partly by genetics, multiple studies have employed genetic scores to explore the role of oxidative stress in human disease. [...] Read more.

The developing brain is highly sensitive to environmental disturbances, and adverse exposures can act through oxidative stress. Given that oxidative stress susceptibility is determined partly by genetics, multiple studies have employed genetic scores to explore the role of oxidative stress in human disease. However, traditional approaches to genetic score construction face a range of challenges, including a lack of interpretability, bias towards the disease outcome, and often overfitting to the study they were derived on. Here, we develop an alternative strategy by first generating a genetic pathway function score for oxidative stress (gPFS^ox) based on the transcriptional activity levels of the oxidative stress response pathway in brain and other tissue types. Then, in the Barwon Infant Study (BIS), a population-based birth cohort (n = 1074), we show that a high gPFS^ox, indicating reduced ability to counter oxidative stress, is linked to higher autism spectrum disorder risk and higher parent-reported autistic traits at age 4 years, with AOR values (per 2 additional pro-oxidant alleles) of 2.10 (95% CI (1.12, 4.11); p = 0.024) and 1.42 (95% CI (1.02, 2.01); p = 0.041), respectively. Past work in BIS has reported higher prenatal phthalate exposure at 36 weeks of gestation associated with offspring autism spectrum disorder. In this study, we examine combined effects and show a consistent pattern of increased neurodevelopmental problems for individuals with both a high gPFS^ox and high prenatal phthalate exposure across a range of outcomes, including high gPFS^ox and high DEHP levels against autism spectrum disorder (attributable proportion due to interaction 0.89; 95% CI (0.62, 1.16); p < 0.0001). The results highlight the utility of this novel functional genetic score and add to the growing evidence implicating gestational phthalate exposure in adverse neurodevelopment. Full article

(This article belongs to the Special Issue Oxidative Stress and Neuroinflammation in Neurological and Neurodegenerative Disorders)

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13 pages, 4006 KiB

Open AccessArticle

Hypothiocyanous Acid Disrupts the Barrier Function of Brain Endothelial Cells

by Eveline van Leeuwen, Mark B. Hampton and Leon C. D. Smyth

Antioxidants 2022, 11(4), 608; https://doi.org/10.3390/antiox11040608 - 22 Mar 2022

Cited by 3 | Viewed by 2587

Abstract

Inflammation is a common feature of neurological diseases. During neuroinflammation, neutrophils are recruited to the brain vasculature, where myeloperoxidase can produce hypochlorous acid and the less well-studied oxidant hypothiocyanous acid (HOSCN). In this study, we exposed primary brain endothelial cells (BECs) to HOSCN [...] Read more.

Inflammation is a common feature of neurological diseases. During neuroinflammation, neutrophils are recruited to the brain vasculature, where myeloperoxidase can produce hypochlorous acid and the less well-studied oxidant hypothiocyanous acid (HOSCN). In this study, we exposed primary brain endothelial cells (BECs) to HOSCN and observed a rapid loss of transendothelial electrical resistance (TEER) at sublethal concentrations. Decreased barrier function was associated with a loss of tight junctions at cellular contacts and a concomitant loss of dynamic microtubules. Both tight junction and cytoskeletal disruptions were visible within 30 min of exposure, whereas significant loss of TEER took more than 1 h. The removal of the HOSCN after 30 min prevented subsequent barrier dysfunction. These results indicate that BECs are sensitive to HOSCN, resulting in the eventual loss of barrier function. We hypothesise that this mechanism may be relevant in neutrophil transmigration, with HOSCN facilitating blood–brain barrier opening at the sites of egress. Furthermore, this mechanism may be a way through which neutrophils, residing in the vasculature, can influence neuroinflammation in diseases. Full article

(This article belongs to the Special Issue Oxidative Stress and Neuroinflammation in Neurological and Neurodegenerative Disorders)

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14 pages, 12594 KiB

Open AccessArticle

Membrane-Free Stem Cells and Pyridoxal 5′-Phosphate Synergistically Enhance Cognitive Function in Alzheimer’s Disease Mouse Model

by Ji Myung Choi, Hye Sook Park, Mei Tong He, Young Sil Kim, Hyun Young Kim, Ah Young Lee and Eun Ju Cho

Antioxidants 2022, 11(3), 601; https://doi.org/10.3390/antiox11030601 - 21 Mar 2022

Cited by 7 | Viewed by 2664

Abstract

Accumulation of amyloid beta (Aβ) is a major pathological hallmark of Alzheimer’s disease (AD). In this study, we evaluated the protective effect of membrane-free stem cell extract (MFSCE), which is a component of adipose-tissue-derived stem cells, on cognitive impairment in Aβ_25–35-injected [...] Read more.

Accumulation of amyloid beta (Aβ) is a major pathological hallmark of Alzheimer’s disease (AD). In this study, we evaluated the protective effect of membrane-free stem cell extract (MFSCE), which is a component of adipose-tissue-derived stem cells, on cognitive impairment in Aβ_25–35-injected AD mice. The ICR mice were i.c.v. injected with Aβ_25–35 and then treated with MFSCE for 14 days (i.p.). The Aβ_25–35-injected mice showed deficits in spatial and object perception abilities, whereas treatment with MFSCE inhibited Aβ_25–35-induced learning and memory impairment in the T-maze, novel object recognition, and Morris water maze tests. Moreover, Aβ_25–35-induced lipid peroxidation and nitric oxide overproduction were attenuated by treatment with MFSCE. These antioxidant effects of MFSCE were related to the inhibition of the apoptotic signaling pathway. In particular, the combination treatment of MFSCE and pyridoxal 5′-phosphate (PLP) showed greater suppression of Bax and cleaved caspase-3 protein expression compared to the MFSCE- or PLP-only treatment. Furthermore, the MFSCE and PLP combination significantly downregulated the amyloidogenic-pathway-related protein expressions, such as amyloid precursor protein, presenilin 1, and presenilin 2. Therefore, the MFSCE and PLP combination may synergistically prevent Aβ_25–35-induced neuronal apoptosis and amyloidogenesis, which contributes to cognitive improvement and has potential therapeutic implications for AD patients. Full article

(This article belongs to the Special Issue Oxidative Stress and Neuroinflammation in Neurological and Neurodegenerative Disorders)

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12 pages, 306 KiB

Open AccessArticle

Serum Trace Elements Concentrations in Patients with Restless Legs Syndrome

by Félix Javier Jiménez-Jiménez, Pedro Ayuso, Hortensia Alonso-Navarro, Marisol Calleja, Mónica Díez-Fairén, Ignacio Álvarez, Pau Pastor, José Francisco Plaza-Nieto, Santiago Navarro-Muñoz, Laura Turpín-Fenoll, Jorge Millán-Pascual, Marta Recio-Bermejo, Rafael García-Ruiz, Esteban García-Albea, José A. G. Agúndez and Elena García-Martín

Antioxidants 2022, 11(2), 272; https://doi.org/10.3390/antiox11020272 - 29 Jan 2022

Cited by 10 | Viewed by 5055

Abstract

Increased brain and serum zinc levels in patients with idiopathic restless legs syndrome (idiopathic RLS or iRLS) were described when compared with controls, suggesting a possible role of zinc in the pathogenesis of this disease. However, serum magnesium, calcium, manganese, iron, and copper [...] Read more.

Increased brain and serum zinc levels in patients with idiopathic restless legs syndrome (idiopathic RLS or iRLS) were described when compared with controls, suggesting a possible role of zinc in the pathogenesis of this disease. However, serum magnesium, calcium, manganese, iron, and copper levels of RLS patients were similar to controls, suggesting a specific impairment of zinc-dependent metabolism in RLS. The aim of this study is to assess the serum concentrations of trace elements involved in oxidative stress or causing peripheral nerve toxicity in a large series of patients with iRLS and controls. We determined serum levels of iron, copper, manganese, zinc, magnesium, selenium, calcium, aluminium, lead, cadmium, arsenic and mercury in 100 patients diagnosed with iRLS and in 110 age- and sex-matched controls using Inductively Coupled Plasma Mass Spectrometry. Serum copper, magnesium, selenium, and calcium concentrations were significantly higher in RLS patients than in controls. These differences were observed both in men and women. There were no major correlations between serum trace metal concentrations and age at onset of RLS or RLS severity, nor was there any association with a family history of RLS or drug response. This study shows an association between increased serum concentrations of copper, magnesium, selenium, and calcium with RLS in a Spanish Caucasian population and does not confirm the previously reported increase in serum zinc concentrations in patients suffering from this disease, suggesting that the different accuracy of the analytical methods used could have influenced the inconsistent results found in the literature. Full article

(This article belongs to the Special Issue Oxidative Stress and Neuroinflammation in Neurological and Neurodegenerative Disorders)

16 pages, 6583 KiB

Open AccessArticle

Umuhengerin Neuroprotective Effects in Streptozotocin-Induced Alzheimer’s Disease Mouse Model via Targeting Nrf2 and NF-Kβ Signaling Cascades

by Alaa Sirwi, Nesrine S. El Sayed, Hossam M. Abdallah, Sabrin R. M. Ibrahim, Gamal A. Mohamed, Ali M. El-Halawany, Martin K. Safo and Nora O. Abdel Rasheed

Antioxidants 2021, 10(12), 2011; https://doi.org/10.3390/antiox10122011 - 18 Dec 2021

Cited by 16 | Viewed by 3551

Abstract

Alzheimer’s disease (AD) is the most common type of dementia and is characterized by advanced cognitive deterioration, deposition of Aβ (amyloid-beta), and the formation of neurofibrillary tangles. Administration of streptozotocin (STZ) via the intracerebroventricular (ICV) route is a reliable model resembling sporadic AD [...] Read more.

Alzheimer’s disease (AD) is the most common type of dementia and is characterized by advanced cognitive deterioration, deposition of Aβ (amyloid-beta), and the formation of neurofibrillary tangles. Administration of streptozotocin (STZ) via the intracerebroventricular (ICV) route is a reliable model resembling sporadic AD (SAD) associated neuropathological changes. The present study was undertaken to explore the neuroprotective effects of the methoxy flavonoid, umuhengerin, in an STZ-induced SAD mouse model as a potential therapy for AD. Mice were injected once with STZ (3 mg/kg, ICV), followed by daily administration of umuhengerin (orally, 30 mg/kg) or the positive control donepezil (orally, 2.5 mg/kg) for 21 days. The pharmacological activity of umuhengerin was assessed through estimation of oxidative stress and inflammatory markers via mouse ELISA kits, Western blot analysis, and brain histopathological examination. Morris water maze test was also conducted to investigate umuhengerin-induced cognitive enhancement. The results showed that umuhengerin attenuated STZ-produced neuroinflammation and oxidative stress with a notable rise in the expression of Nrf2 (nuclear factor erythroid 2-related factor 2). In contrast, it downregulated Keap-1 (Kelch-like ECH associated protein 1), as well as elevated brain contents of GSH (reduced glutathione) and HO-1 (heme oxygenase-1). STZ-injected animals receiving umuhengerin showed marked downregulation of the nuclear factor kappa beta (NF-Kβp65) and noticeable increment in the expression of its inhibitor kappa beta alpha protein (IKβα), as well as prominent reduction in malondialdehyde (MDA), H₂O₂ (hydrogen peroxide), and TNF-α (tumor-necrosis factor-alpha) contents. Β-secretase protein expression and acetylcholinesterase (AchE) activity were also diminished upon umuhengerin injection in the STZ group, leading to decreased Aβ formation and cognitive improvement, respectively. In conclusion, umuhengerin neuroprotective effects were comparable to the standard drug donepezil; thus, it could be an alternative approach for AD management. Full article

(This article belongs to the Special Issue Oxidative Stress and Neuroinflammation in Neurological and Neurodegenerative Disorders)

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8 pages, 507 KiB

Open AccessArticle

Assessment of Screening Approach in Early and Differential Alzheimer’s Disease Diagnosis

by Laura Ferré-González, Carmen Peña-Bautista, Lourdes Álvarez-Sánchez, Inés Ferrer-Cairols, Miguel Baquero and Consuelo Cháfer-Pericás

Antioxidants 2021, 10(11), 1662; https://doi.org/10.3390/antiox10111662 - 22 Oct 2021

Cited by 2 | Viewed by 2163

Abstract

Background: Alzheimer’s disease (AD) is the leading cause of dementia in the elderly population. Currently, diagnosis is based on invasive and expensive techniques, so there is a growing need to look for other possible tests, as well as carry out clinical validation. Studies [...] Read more.

Background: Alzheimer’s disease (AD) is the leading cause of dementia in the elderly population. Currently, diagnosis is based on invasive and expensive techniques, so there is a growing need to look for other possible tests, as well as carry out clinical validation. Studies from the literature showed potential diagnosis models, including some AD risk factors (age, gender, ApoE-ε4 genotype) and other variables (biomarkers levels, neuroimaging). Specifically, a recent model was performed from lipid peroxidation compounds in plasma samples to identify patients with early AD. However, there is a lack of studies about clinical validation of these preliminary diagnosis models. Methods: Plasma samples from participants classified into AD (n = 61), non-AD (n = 17), and healthy (n = 44) were analyzed. In fact, lipid peroxidation compounds were determined by liquid chromatography and mass spectrometry. Then, a previously developed diagnosis model was clinically validated, evaluating some diagnosis indexes. Results: The validation of the preliminary diagnosis model showed satisfactory diagnosis indexes (accuracy 77%, sensitivity 89%, specificity 61%, diagnostic odds ratio 12.5, positive predictive value 76%). Next, a useful screening tool, including the ApoE genotype, was developed, identifying patients with a higher risk of developing AD and improving the corresponding diagnosis indexes (accuracy 82%, sensitivity 81%, specificity 85%, diagnostic odds ratio 23.2, positive predictive value 90.5%). Conclusion: A new screening approach could improve the early, minimally invasive, and differential AD diagnosis in the general population. Full article

(This article belongs to the Special Issue Oxidative Stress and Neuroinflammation in Neurological and Neurodegenerative Disorders)

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24 pages, 5530 KiB

Open AccessArticle

L-Methionine Protects against Oxidative Stress and Mitochondrial Dysfunction in an In Vitro Model of Parkinson’s Disease

by Mariano Catanesi, Laura Brandolini, Michele d’Angelo, Elisabetta Benedetti, Maria Grazia Tupone, Margherita Alfonsetti, Enrico Cabri, Daniela Iaconis, Maddalena Fratelli, Annamaria Cimini, Vanessa Castelli and Marcello Allegretti

Antioxidants 2021, 10(9), 1467; https://doi.org/10.3390/antiox10091467 - 15 Sep 2021

Cited by 27 | Viewed by 6705

Abstract

Methionine is an aliphatic, sulfur-containing, essential amino acid that has been demonstrated to have crucial roles in metabolism, innate immunity, and activation of endogenous antioxidant enzymes, including methionine sulfoxide reductase A/B and the biosynthesis of glutathione to counteract oxidative stress. Still, methionine restriction [...] Read more.

Methionine is an aliphatic, sulfur-containing, essential amino acid that has been demonstrated to have crucial roles in metabolism, innate immunity, and activation of endogenous antioxidant enzymes, including methionine sulfoxide reductase A/B and the biosynthesis of glutathione to counteract oxidative stress. Still, methionine restriction avoids altered methionine/transmethylation metabolism, thus reducing DNA damage and possibly avoiding neurodegenerative processes. In this study, we wanted to study the preventive effects of methionine in counteracting 6-hydroxydopamine (6-OHDA)-induced injury. In particular, we analyzed the protective effects of the amino acid L-methionine in an in vitro model of Parkinson’s disease and dissected the underlying mechanisms compared to the known antioxidant taurine to gain insights into the potential of methionine treatment in slowing the progression of the disease by maintaining mitochondrial functionality. In addition, to ascribe the effects of methionine on mitochondria and oxidative stress, methionine sulfoxide was used in place of methionine. The data obtained suggested that an L-methionine-enriched diet could be beneficial during aging to protect neurons from oxidative imbalance and mitochondrial dysfunction, thus preventing the progression of neurodegenerative processes. Full article

(This article belongs to the Special Issue Oxidative Stress and Neuroinflammation in Neurological and Neurodegenerative Disorders)

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19 pages, 3698 KiB

Open AccessArticle

NADPH-Oxidase, Rho-Kinase and Autophagy Mediate the (Pro)renin-Induced Pro-Inflammatory Microglial Response and Enhancement of Dopaminergic Neuron Death

by Andrea Lopez-Lopez, Begoña Villar-Cheda, Aloia Quijano, Pablo Garrido-Gil, María Garcia-Garrote, Carmen Díaz-Ruiz, Ana Muñoz and José L. Labandeira-Garcia

Antioxidants 2021, 10(9), 1340; https://doi.org/10.3390/antiox10091340 - 25 Aug 2021

Cited by 5 | Viewed by 3055

Abstract

Dysregulation of the tissue renin–angiotensin system (RAS) is involved in tissue oxidative and inflammatory responses. Among RAS components, renin, its precursor (pro)renin and its specific receptor (PRR) have been less investigated, particularly in the brain. We previously showed the presence of PRR in [...] Read more.

Dysregulation of the tissue renin–angiotensin system (RAS) is involved in tissue oxidative and inflammatory responses. Among RAS components, renin, its precursor (pro)renin and its specific receptor (PRR) have been less investigated, particularly in the brain. We previously showed the presence of PRR in neurons and glial cells in the nigrostriatal system of rodents and primates, including humans. Now, we used rat and mouse models and cultures of BV2 and primary microglial cells to study the role of PRR in microglial pro-inflammatory responses. PRR was upregulated in the nigral region, particularly in microglia during the neuroinflammatory response. In the presence of the angiotensin type-1 receptor blocker losartan, to exclude angiotensin-related effects, treatment of microglial cells with (pro)renin induces the expression of microglial pro-inflammatory markers, which is mediated by upregulation of NADPH-oxidase and Rho-kinase activities, downregulation of autophagy and upregulation of inflammasome activity. Conditioned medium from (pro)renin-treated microglia increased dopaminergic cell death relative to medium from non-treated microglia. However, these effects were blocked by pre-treatment of microglia with the Rho-kinase inhibitor fasudil. Activation of microglial PRR enhances the microglial pro-inflammatory response and deleterious effects of microglia on dopaminergic cells, and microglial NADPH-oxidase, Rho-Kinase and autophagy are involved in this process. Full article

(This article belongs to the Special Issue Oxidative Stress and Neuroinflammation in Neurological and Neurodegenerative Disorders)

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15 pages, 13184 KiB

Open AccessFeature PaperArticle

TNF-α Receptor Inhibitor Alleviates Metabolic and Inflammatory Changes in a Rat Model of Ischemic Stroke

by Shih-Yi Lin, Ya-Yu Wang, Cheng-Yi Chang, Chih-Cheng Wu, Wen-Ying Chen, Su-Lan Liao and Chun-Jung Chen

Antioxidants 2021, 10(6), 851; https://doi.org/10.3390/antiox10060851 - 26 May 2021

Cited by 29 | Viewed by 3715

Abstract

Hyperglycemia and inflammation, with their augmented interplay, are involved in cases of stroke with poor outcomes. Interrupting this vicious cycle thus has the potential to prevent stroke disease progression. Tumor necrosis factor-α (TNF-α) is an emerging molecule, which has inflammatory and metabolic roles. [...] Read more.

Hyperglycemia and inflammation, with their augmented interplay, are involved in cases of stroke with poor outcomes. Interrupting this vicious cycle thus has the potential to prevent stroke disease progression. Tumor necrosis factor-α (TNF-α) is an emerging molecule, which has inflammatory and metabolic roles. Studies have shown that TNF-α receptor inhibitor R-7050 possesses neuroprotective, antihyperglycemic, and anti-inflammatory effects. Using a rat model of permanent cerebral ischemia, pretreatment with R-7050 offered protection against poststroke neurological deficits, brain infarction, edema, oxidative stress, and caspase 3 activation. In the injured cortical tissues, R-7050 reversed the activation of TNF receptor-I (TNFRI), NF-κB, and interleukin-6 (IL-6), as well as the reduction of zonula occludens-1 (ZO-1). In the in vitro study on bEnd.3 endothelial cells, R-7050 reduced the decline of ZO-1 levels after TNF-α-exposure. R-7050 also reduced the metabolic alterations occurring after ischemic stroke, such as hyperglycemia and increased plasma corticosterone, free fatty acids, C reactive protein, and fibroblast growth factor-15 concentrations. In the gastrocnemius muscles of rats with stroke, R-7050 improved activated TNFRI/NF-κB, oxidative stress, and IL-6 pathways, as well as impaired insulin signaling. Overall, our findings highlight a feasible way to combat stroke disease based on an anti-TNF therapy that involves anti-inflammatory and metabolic mechanisms. Full article

(This article belongs to the Special Issue Oxidative Stress and Neuroinflammation in Neurological and Neurodegenerative Disorders)

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Review

Jump to: Research

25 pages, 1156 KiB

Open AccessReview

Possible Effects and Mechanisms of Dietary Natural Products and Nutrients on Depression and Anxiety: A Narrative Review

by Si-Xia Wu, Jiahui Li, Dan-Dan Zhou, Ruo-Gu Xiong, Si-Yu Huang, Adila Saimaiti, Ao Shang and Hua-Bin Li

Antioxidants 2022, 11(11), 2132; https://doi.org/10.3390/antiox11112132 - 28 Oct 2022

Cited by 22 | Viewed by 5084

Abstract

Depression and anxiety are severe public health problems and have attracted more and more attention from researchers of food science and nutrition. Dietary natural products and nutrients, such as fish, coffee, tea, n-3 PUFA, lycopene, and dietary fiber, could play a vital role [...] Read more.

Depression and anxiety are severe public health problems and have attracted more and more attention from researchers of food science and nutrition. Dietary natural products and nutrients, such as fish, coffee, tea, n-3 PUFA, lycopene, and dietary fiber, could play a vital role in the prevention and management of these diseases. The potential mechanisms of action mainly include inhibiting inflammation, ameliorating oxidative stress, modulating the microbiota–gut–brain axis, suppressing hypothalamic–pituitary–adrenal axis hyperactivity, and regulating the levels of monoamine neurotransmitters. In this narrative review, we summarize the most recent advancements regarding the effects of dietary natural products and nutrients on depression and anxiety, and their underlying mechanisms are discussed. We hope that this paper can provide a better understanding of the anti-depressive and anxiolytic action of dietary natural products, and that it is also helpful for developing dietary natural products for functional food, dietary supplements, or auxiliary agents for the prevention and management of these diseases. Full article

(This article belongs to the Special Issue Oxidative Stress and Neuroinflammation in Neurological and Neurodegenerative Disorders)

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13 pages, 633 KiB

Open AccessReview

A Leaky Blood–Brain Barrier to Fibrinogen Contributes to Oxidative Damage in Alzheimer’s Disease

by James G. McLarnon

Antioxidants 2022, 11(1), 102; https://doi.org/10.3390/antiox11010102 - 31 Dec 2021

Cited by 28 | Viewed by 3223

Abstract

The intactness of blood–brain barrier (BBB) is compromised in Alzheimer’s disease (AD). Importantly, evidence suggests that the perturbation and abnormalities appearing in BBB can manifest early in the progression of the disease. The disruption of BBB allows extravasation of the plasma protein, fibrinogen, [...] Read more.

The intactness of blood–brain barrier (BBB) is compromised in Alzheimer’s disease (AD). Importantly, evidence suggests that the perturbation and abnormalities appearing in BBB can manifest early in the progression of the disease. The disruption of BBB allows extravasation of the plasma protein, fibrinogen, to enter brain parenchyma, eliciting immune reactivity and response. The presence of amyloid-β (Aβ) peptide leads to the formation of abnormal aggregates of fibrin resistant to degradation. Furthermore, Aβ deposits act on the contact system of blood coagulation, altering levels of thrombin, fibrin clots and neuroinflammation. The neurovascular unit (NVU) comprises an ensemble of brain cells which interact with infiltrating fibrinogen. In particular, interaction of resident immune cell microglia with fibrinogen, fibrin and Aβ results in the production of reactive oxygen species (ROS), a neurotoxic effector in AD brain. Overall, fibrinogen infiltration through a leaky BBB in AD animal models and in human AD tissue is associated with manifold abnormalities including persistent fibrin aggregation and clots, microglial-mediated production of ROS and diminished viability of neurons and synaptic connectivity. An objective of this review is to better understand how processes associated with BBB leakiness to fibrinogen link vascular pathology with neuronal and synaptic damage in AD. Full article

(This article belongs to the Special Issue Oxidative Stress and Neuroinflammation in Neurological and Neurodegenerative Disorders)

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18 pages, 1548 KiB

Open AccessReview

The Alteration of Chloride Homeostasis/GABAergic Signaling in Brain Disorders: Could Oxidative Stress Play a Role?

by Provvidenza M. Abruzzo, Cristina Panisi and Marina Marini

Antioxidants 2021, 10(8), 1316; https://doi.org/10.3390/antiox10081316 - 21 Aug 2021

Cited by 14 | Viewed by 3899

Abstract

In neuronal precursors and immature neurons, the depolarizing (excitatory) effect of γ-Aminobutyric acid (GABA) signaling is associated with elevated [Cl⁻]_i; as brain cells mature, a developmental switch occurs, leading to the decrease of [Cl⁻]_i and to [...] Read more.

In neuronal precursors and immature neurons, the depolarizing (excitatory) effect of γ-Aminobutyric acid (GABA) signaling is associated with elevated [Cl⁻]_i; as brain cells mature, a developmental switch occurs, leading to the decrease of [Cl⁻]_i and to the hyperpolarizing (inhibitory) effect of GABAergic signaling. [Cl⁻]_i is controlled by two chloride co-transporters: NKCC1, which causes Cl⁻ to accumulate into the cells, and KCC2, which extrudes it. The ontogenetic upregulation of the latter determines the above-outlined switch; however, many other factors contribute to the correct [Cl⁻]_i in mature neurons. The dysregulation of chloride homeostasis is involved in seizure generation and has been associated with schizophrenia, Down’s Syndrome, Autism Spectrum Disorder, and other neurodevelopmental disorders. Recently, much effort has been put into developing new drugs intended to inhibit NKCC1 activity, while no attention has been paid to the origin of [Cl⁻]_i dysregulation. Our study examines the pathophysiology of Cl⁻ homeostasis and focuses on the impact of oxidative stress (OS) and inflammation on the activity of Cl⁻ co-transporters, highlighting the relevance of OS in numerous brain abnormalities and diseases. This hypothesis supports the importance of primary prevention during pregnancy. It also integrates the therapeutic framework addressed to restore normal GABAergic signaling by counteracting the alteration in chloride homeostasis in central nervous system (CNS) cells, aiming at limiting the use of drugs that potentially pose a health risk. Full article

(This article belongs to the Special Issue Oxidative Stress and Neuroinflammation in Neurological and Neurodegenerative Disorders)

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