Antioxidants

Research

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10 pages, 1985 KiB

Open AccessArticle

Mutant Huntingtin Derails Cysteine Metabolism in Huntington’s Disease at Both Transcriptional and Post-Translational Levels

by Bindu D. Paul, Juan I. Sbodio and Solomon H. Snyder

Antioxidants 2022, 11(8), 1470; https://doi.org/10.3390/antiox11081470 - 27 Jul 2022

Cited by 4 | Viewed by 1547

Abstract

Cysteine is a semi-essential amino acid that not only plays an essential role as a component of protein synthesis, but also in the generation of numerous sulfur-containing molecules such as the antioxidant glutathione and coenzyme A. We previously showed that the metabolism of [...] Read more.

Cysteine is a semi-essential amino acid that not only plays an essential role as a component of protein synthesis, but also in the generation of numerous sulfur-containing molecules such as the antioxidant glutathione and coenzyme A. We previously showed that the metabolism of cysteine is dysregulated in Huntington’s disease (HD), a neurodegenerative disorder triggered by the expansion of polyglutamine repeats in the protein huntingtin. In this study, we showed that cysteine metabolism is compromised at multiple levels in HD, both transcriptional and post-translational. Accordingly, restoring cysteine homeostasis may be beneficial in HD. Full article

(This article belongs to the Special Issue Oxidative Stress in Neurons)

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11 pages, 1770 KiB

Open AccessArticle

Potential Neurotoxic Effects of Glioblastoma-Derived Exosomes in Primary Cultures of Cerebellar Neurons via Oxidant Stress and Glutathione Depletion

by Sidika Genc, Manuela Pennisi, Yesim Yeni, Serkan Yildirim, Giuseppe Gattuso, Meric A. Altinoz, Ali Taghizadehghalehjoughi, Ismail Bolat, Aristidis Tsatsakis, Ahmet Hacımüftüoğlu and Luca Falzone

Antioxidants 2022, 11(7), 1225; https://doi.org/10.3390/antiox11071225 - 23 Jun 2022

Cited by 14 | Viewed by 2556

Abstract

High-grade gliomas are the most fatal brain tumors. Grade 4 gliomas are called glioblastoma multiforme (GBM), which are associated with the poorest survival and a 5-year survival rate of less than 4%. Many patients with GBM developed concomitant cognitive dysfunctions and epilepsy. Although [...] Read more.

High-grade gliomas are the most fatal brain tumors. Grade 4 gliomas are called glioblastoma multiforme (GBM), which are associated with the poorest survival and a 5-year survival rate of less than 4%. Many patients with GBM developed concomitant cognitive dysfunctions and epilepsy. Although the cognitive decline is well defined in glioblastomas, the neurotoxic factors underlying this pathology are not well understood in GBM patients. In this study, we aimed to investigate whether GBM-derived exosomes play a role in neuronal toxicity. For this purpose, exosomes obtained from T98G and U373 GBM cells were applied to primary neuron culture at different concentrations. Subsequently, MTT, LDH, GSH, TAS, and TOS tests were performed. Both GBM-derived exosomes induced a dose-dependent and statistically significant increase of LDH release in cerebellar neurons. MTT assay revealed as both T98G and U373 GBM-derived exosomes induced dose-dependent neurotoxic effects in cerebellar neurons. To the best of our knowledge, this study is the first study demonstrating the toxic potential of GBM-derived exosomes to primary neurons, which may explain the peritumoral edema and cognitive decline in GBM patients. Full article

(This article belongs to the Special Issue Oxidative Stress in Neurons)

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11 pages, 1287 KiB

Open AccessCommunication

The Non-Specific Drp1 Inhibitor Mdivi-1 Has Modest Biochemical Antioxidant Activity

by Evan A. Bordt, Naibo Zhang, Jaylyn Waddell and Brian M. Polster

Antioxidants 2022, 11(3), 450; https://doi.org/10.3390/antiox11030450 - 24 Feb 2022

Cited by 13 | Viewed by 3059

Abstract

Mitochondrial division inhibitor-1 (mdivi-1), a non-specific inhibitor of Drp1-dependent mitochondrial fission, is neuroprotective in numerous preclinical disease models. These include rodent models of Alzheimer’s disease and ischemic or traumatic brain injury. Among its Drp1-independent actions, the compound was found to suppress mitochondrial Complex [...] Read more.

Mitochondrial division inhibitor-1 (mdivi-1), a non-specific inhibitor of Drp1-dependent mitochondrial fission, is neuroprotective in numerous preclinical disease models. These include rodent models of Alzheimer’s disease and ischemic or traumatic brain injury. Among its Drp1-independent actions, the compound was found to suppress mitochondrial Complex I-dependent respiration but with less resultant mitochondrial reactive oxygen species (ROS) emission compared with the classical Complex I inhibitor rotenone. We employed two different methods of quantifying Trolox-equivalent antioxidant capacity (TEAC) to test the prediction that mdivi-1 can directly scavenge free radicals. Mdivi-1 exhibited moderate antioxidant activity in the 2,2′-azinobis (3-ethylbenzothiazoline 6-sulfonate) (ABTS) assay. Half-maximal ABTS radical depletion was observed at ~25 μM mdivi-1, equivalent to that achieved by ~12.5 μM Trolox. Mdivi-1 also showed antioxidant activity in the α, α-diphenyl-β-picrylhydrazyl (DPPH) assay. However, mdivi-1 exhibited a reduced capacity to deplete the DPPH radical, which has a more sterically hindered radical site compared with ABTS, with 25 μM mdivi-1 displaying only 0.8 μM Trolox equivalency. Both assays indicate that mdivi-1 possesses biochemical antioxidant activity but with modest potency relative to the vitamin E analog Trolox. Future studies are needed to evaluate whether the ability of mdivi-1 to directly scavenge free radicals contributes to its mechanisms of neuroprotection. Full article

(This article belongs to the Special Issue Oxidative Stress in Neurons)

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15 pages, 3241 KiB

Open AccessArticle

Structure–Activity Relationships and Transcriptomic Analysis of Hypoxia-Inducible Factor Prolyl Hydroxylase Inhibitors

by Andrey A. Poloznikov, Sergey V. Nikulin, Dmitry M. Hushpulian, Anna Yu. Khristichenko, Andrey I. Osipyants, Andrey F. Asachenko, Olga V. Shurupova, Svyatoslav S. Savin, Sue H. Lee, Irina N. Gaisina, Gregory R. J. Thatcher, Anthony Narciso, Eric P. Chang, Sergey V. Kazakov, Nancy Krucher, Vladimir I. Tishkov, Bobby Thomas and Irina G. Gazaryan

Antioxidants 2022, 11(2), 220; https://doi.org/10.3390/antiox11020220 - 24 Jan 2022

Cited by 2 | Viewed by 3789

Abstract

To evaluate the differences in action of commercially available 2-oxoglutarate mimetics and “branched-tail” oxyquinoline inhibitors of hypoxia-inducible factor prolyl hydroxylase (HIF PHD), the inhibitors’ IC₅₀ values in the activation of HIF1 ODD-luciferase reporter were selected for comparative transcriptomics. Structure–activity relationship and computer [...] Read more.

To evaluate the differences in action of commercially available 2-oxoglutarate mimetics and “branched-tail” oxyquinoline inhibitors of hypoxia-inducible factor prolyl hydroxylase (HIF PHD), the inhibitors’ IC₅₀ values in the activation of HIF1 ODD-luciferase reporter were selected for comparative transcriptomics. Structure–activity relationship and computer modeling for the oxyquinoline series of inhibitors led to the identification of novel inhibitors, which were an order of magnitude more active in the reporter assay than roxadustat and vadadustat. Unexpectedly, 2-methyl-substitution in the oxyquinoline core of the best HIF PHD inhibitor was found to be active in the reporter assay and almost equally effective in the pretreatment paradigm of the oxygen-glucose deprivation in vitro model. Comparative transcriptomic analysis of the signaling pathways induced by HIF PHD inhibitors showed high potency of the two novel oxyquinoline inhibitors (#4896-3249 and #5704-0720) at 2 μM concentrations matching the effect of 30 μM roxadustat and 500 μM dimethyl oxalyl glycine in inducing HIF1 and HIF2-linked pathways. The two oxyquinoline inhibitors exerted the same activation of HIF-triggered glycolytic pathways but opposite effects on signaling pathways linked to alternative substrates of HIF PHD 1 and 3, such as p53, NF-κB, and ATF4. This finding can be interpreted as the specificity of the 2-methyl-substitute variant for HIF PHD2. Full article

(This article belongs to the Special Issue Oxidative Stress in Neurons)

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15 pages, 45107 KiB

Open AccessArticle

γ-Glutamyl-Transpeptidase-Resistant Glutathione Analog Attenuates Progression of Alzheimer’s Disease-like Pathology and Neurodegeneration in a Mouse Model

by Ye In Christopher Kwon, Wei Xie, Haizhou Zhu, Jiashu Xie, Keaton Shinn, Nicholas Juckel, Robert Vince, Swati S. More and Michael K. Lee

Antioxidants 2021, 10(11), 1796; https://doi.org/10.3390/antiox10111796 - 10 Nov 2021

Cited by 7 | Viewed by 2114

Abstract

Oxidative stress in Alzheimer’s disease (AD) is mediated, in part, by the loss of glutathione (GSH). Previous studies show that γ-glutamyl transpeptidase (GGT)-resistant GSH analog, Ψ-GSH, improves brain GSH levels, reduces oxidative stress markers in brains of APP/PS1 transgenic mice, a mouse model [...] Read more.

Oxidative stress in Alzheimer’s disease (AD) is mediated, in part, by the loss of glutathione (GSH). Previous studies show that γ-glutamyl transpeptidase (GGT)-resistant GSH analog, Ψ-GSH, improves brain GSH levels, reduces oxidative stress markers in brains of APP/PS1 transgenic mice, a mouse model of AD, and attenuates early memory deficits in the APP/PS1 model. Herein, we examined whether Ψ-GSH can attenuate the disease progression when administered following the onset of AD-like pathology in vivo. Cohorts of APP/PS1 mice were administered Ψ-GSH for 2 months starting at 8 month or 12 months of age. We show that Ψ-GSH treatment reduces indices of oxidative stress in older mice by restoration of enzyme glyoxalase-1 (Glo-1) activity and reduces levels of insoluble Aβ. Quantitative neuropathological analyses show that Ψ-GSH treatment significantly reduces Aβ deposition and brain inflammation in APP/PS1 mice compared to vehicle-treated mice. More importantly, Ψ-GSH treatment attenuated the progressive loss of cortical TH+ afferents and the loss of TH+ neurons in the locus coeruleus (LC). Collectively, the results show that Ψ-GSH exhibits significant antioxidant activity in aged APP/PS1 mice and chronic Ψ-GSH treatment administered after the onset of AD pathology can reverse/slow further progression of AD-like pathology and neurodegeneration in vivo. Full article

(This article belongs to the Special Issue Oxidative Stress in Neurons)

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11 pages, 2551 KiB

Open AccessArticle

Sigma 1 Receptor Co-Localizes with NRF2 in Retinal Photoreceptor Cells

by Shannon R. Barwick, Mevish S. Siddiq, Jing Wang, Haiyan Xiao, Brendan Marshall, Elizabeth Perry and Sylvia B. Smith

Antioxidants 2021, 10(6), 981; https://doi.org/10.3390/antiox10060981 - 19 Jun 2021

Cited by 9 | Viewed by 2714

Abstract

Sigma 1 receptor (Sig1R), a modulator of cell survival, has emerged as a novel target for retinal degenerative disease. Studies have shown that activation of Sig1R, using the high affinity ligand (+)-pentazocine ((+)-PTZ), improves cone function in a severe retinopathy model. The rescue [...] Read more.

Sigma 1 receptor (Sig1R), a modulator of cell survival, has emerged as a novel target for retinal degenerative disease. Studies have shown that activation of Sig1R, using the high affinity ligand (+)-pentazocine ((+)-PTZ), improves cone function in a severe retinopathy model. The rescue is accompanied by normalization of levels of NRF2, a key transcription factor that regulates the antioxidant response. The interaction of Sig1R with a number of proteins has been investigated; whether it interacts with NRF2, however, is not known. We used co-immunoprecipitation (co-IP), proximity ligation assay (PLA), and electron microscopy (EM) immunodetection methods to investigate this question in the 661W cone photoreceptor cell line. For co-IP experiments, immune complexes were precipitated by protein A/G agarose beads and immunodetected using anti-NRF2 antibody. For PLA, cells were incubated with anti-Sig1R polyclonal and anti-NRF2 monoclonal antibodies, then subsequently with (−)-mouse and (+)-rabbit PLA probes. For EM analysis, immuno-EM gold labeling was performed using nanogold-enhanced labeling with anti-NRF2 and anti-Sig1R antibodies, and data were confirmed using colloidal gold labeling. The co-IP experiment suggested that NRF2 was bound in a complex with Sig1R. The PLA assays detected abundant orange fluorescence in cones, indicating that Sig1R and NRF2 were within 40 nm of each other. EM immunodetection confirmed co-localization of Sig1R with NRF2 in cells and in mouse retinal tissue. This study is the first to report co-localization of Sig1R-NRF2 and supports earlier studies implicating modulation of NRF2 as a mechanism by which Sig1R mediates retinal neuroprotection. Full article

(This article belongs to the Special Issue Oxidative Stress in Neurons)

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12 pages, 2879 KiB

Open AccessArticle

Oxidative Stress Signaling in Blast TBI-Induced Tau Phosphorylation

by Chunyu Wang, Changjuan Shao, Li Zhang, Sandra L. Siedlak, James S. Meabon, Elaine R. Peskind, Yubing Lu, Wenzhang Wang, George Perry, David G. Cook and Xiongwei Zhu

Antioxidants 2021, 10(6), 955; https://doi.org/10.3390/antiox10060955 - 15 Jun 2021

Cited by 10 | Viewed by 2716

Abstract

Traumatic brain injury caused by blast is associated with long-term neuropathological changes including tau phosphorylation and pathology. In this study, we aimed to determine changes in initial tau phosphorylation after exposure to a single mild blast and the potential contribution of oxidative stress [...] Read more.

Traumatic brain injury caused by blast is associated with long-term neuropathological changes including tau phosphorylation and pathology. In this study, we aimed to determine changes in initial tau phosphorylation after exposure to a single mild blast and the potential contribution of oxidative stress response pathways. C57BL/6 mice were exposed to a single blast overpressure (BOP) generated by a compressed gas-driven shock tube that recapitulates battlefield-relevant open-field BOP, and cortical tissues were harvested at different time points up to 24 h after blast for Western blot analysis. We found that BOP caused elevated tau phosphorylation at Ser202/Thr205 detected by the AT8 antibody at 1 h post-blast followed by tau phosphorylation at additional sites (Ser262 and Ser396/Ser404 detected by PHF1 antibody) and conformational changes detected by Alz50 antibody. BOP also induced acute oxidative damage at 1 h post-blast and gradually declined overtime. Interestingly, Extracellular signal-regulated kinase (ERK) and c-Jun N-terminal kinase (JNK) were acutely activated in a similar temporal pattern as the rise and fall in oxidative stress after blast, with p38 showing a similar trend. However, glycogen synthase kinase-3 β (GSK3β) was inhibited at 1 h and remained inhibited for 24 h post blast. These results suggested that mitogen-activated protein kinases (MAPKs) but not GSK3β are likely involved in mediating the effects of oxidative stress on the initial increase of tau phosphorylation following a single mild blast. Full article

(This article belongs to the Special Issue Oxidative Stress in Neurons)

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20 pages, 3746 KiB

Open AccessArticle

Neuroprotective Effect of HIF Prolyl Hydroxylase Inhibition in an In Vitro Hypoxia Model

by Maria Savyuk, Mikhail Krivonosov, Tatiana Mishchenko, Irina Gazaryan, Mikhail Ivanchenko, Anna Khristichenko, Andrey Poloznikov, Dmitry Hushpulian, Sergey Nikulin, Evgeny Tonevitsky, Guzal Abuzarova, Elena Mitroshina and Maria Vedunova

Antioxidants 2020, 9(8), 662; https://doi.org/10.3390/antiox9080662 - 24 Jul 2020

Cited by 17 | Viewed by 3906

Abstract

A novel potent analog of the branched tail oxyquinoline group of hypoxia-inducible factor (HIF) prolyl hydroxylase inhibitors, neuradapt, has been studied in two treatment regimes in an in vitro hypoxia model on murine primary hippocampal cultures. Neuradapt activates the expression of HIF1 and [...] Read more.

A novel potent analog of the branched tail oxyquinoline group of hypoxia-inducible factor (HIF) prolyl hydroxylase inhibitors, neuradapt, has been studied in two treatment regimes in an in vitro hypoxia model on murine primary hippocampal cultures. Neuradapt activates the expression of HIF1 and HIF2 target genes and shows no toxicity up to 20 μM, which is more than an order of magnitude higher than its biologically active concentration. Cell viability, functional activity, and network connectivity between the elements of neuronal networks have been studied using a pairwise correlation analysis of the intracellular calcium fluctuations in the individual cells. An immediate treatment with 1 μM and 15 μM neuradapt right at the onset of hypoxia not only protects from the death, but also maintains the spontaneous calcium activity in nervous cells at the level of the intact cultures. A similar neuroprotective effect in the post-treatment scenario is observed for 15 μM, but not for 1 μM neuradapt. Network connectivity is better preserved with immediate treatment using 1 μM neuradapt than with 15 μM, which is still beneficial. Post-treatment with neuradapt did not restore the network connectivity despite the observation that neuradapt significantly increased cell viability at 1 μM and functional activity at 15 μM. The preservation of cell viability and functional activity makes neuradapt promising for further studies in a post-treatment scenario, since it can be combined with other drugs and treatments restoring the network connectivity of functionally competent cells. Full article

(This article belongs to the Special Issue Oxidative Stress in Neurons)

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Review

Jump to: Research

32 pages, 14552 KiB

Open AccessReview

Harnessing the Therapeutic Potential of the Nrf2/Bach1 Signaling Pathway in Parkinson’s Disease

by Manuj Ahuja, Navneet Ammal Kaidery, Debashis Dutta, Otis C. Attucks, Eliot H. Kazakov, Irina Gazaryan, Mitsuyo Matsumoto, Kazuhiko Igarashi, Sudarshana M. Sharma and Bobby Thomas

Antioxidants 2022, 11(9), 1780; https://doi.org/10.3390/antiox11091780 - 09 Sep 2022

Cited by 11 | Viewed by 3660

Abstract

Parkinson’s disease (PD) is the second most common neurodegenerative movement disorder characterized by a progressive loss of dopaminergic neurons in the substantia nigra pars compacta. Although a complex interplay of multiple environmental and genetic factors has been implicated, the etiology of neuronal death [...] Read more.

Parkinson’s disease (PD) is the second most common neurodegenerative movement disorder characterized by a progressive loss of dopaminergic neurons in the substantia nigra pars compacta. Although a complex interplay of multiple environmental and genetic factors has been implicated, the etiology of neuronal death in PD remains unresolved. Various mechanisms of neuronal degeneration in PD have been proposed, including oxidative stress, mitochondrial dysfunction, neuroinflammation, α-synuclein proteostasis, disruption of calcium homeostasis, and other cell death pathways. While many drugs individually targeting these pathways have shown promise in preclinical PD models, this promise has not yet translated into neuroprotective therapies in human PD. This has consequently spurred efforts to identify alternative targets with multipronged therapeutic approaches. A promising therapeutic target that could modulate multiple etiological pathways involves drug-induced activation of a coordinated genetic program regulated by the transcription factor, nuclear factor E2-related factor 2 (Nrf2). Nrf2 regulates the transcription of over 250 genes, creating a multifaceted network that integrates cellular activities by expressing cytoprotective genes, promoting the resolution of inflammation, restoring redox and protein homeostasis, stimulating energy metabolism, and facilitating repair. However, FDA-approved electrophilic Nrf2 activators cause irreversible alkylation of cysteine residues in various cellular proteins resulting in side effects. We propose that the transcriptional repressor of BTB and CNC homology 1 (Bach1), which antagonizes Nrf2, could serve as a promising complementary target for the activation of both Nrf2-dependent and Nrf2-independent neuroprotective pathways. This review presents the current knowledge on the Nrf2/Bach1 signaling pathway, its role in various cellular processes, and the benefits of simultaneously inhibiting Bach1 and stabilizing Nrf2 using non-electrophilic small molecules as a novel therapeutic approach for PD. Full article

(This article belongs to the Special Issue Oxidative Stress in Neurons)

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17 pages, 910 KiB

Open AccessReview

The Interconnected Mechanisms of Oxidative Stress and Neuroinflammation in Epilepsy

by Anna L. M. Parsons, Eboni M. V. Bucknor, Enrico Castroflorio, Tânia R. Soares, Peter L. Oliver and Daniel Rial

Antioxidants 2022, 11(1), 157; https://doi.org/10.3390/antiox11010157 - 14 Jan 2022

Cited by 37 | Viewed by 4602

Abstract

One of the most important characteristics of the brain compared to other organs is its elevated metabolic demand. Consequently, neurons consume high quantities of oxygen, generating significant amounts of reactive oxygen species (ROS) as a by-product. These potentially toxic molecules cause oxidative stress [...] Read more.

One of the most important characteristics of the brain compared to other organs is its elevated metabolic demand. Consequently, neurons consume high quantities of oxygen, generating significant amounts of reactive oxygen species (ROS) as a by-product. These potentially toxic molecules cause oxidative stress (OS) and are associated with many disorders of the nervous system, where pathological processes such as aberrant protein oxidation can ultimately lead to cellular dysfunction and death. Epilepsy, characterized by a long-term predisposition to epileptic seizures, is one of the most common of the neurological disorders associated with OS. Evidence shows that increased neuronal excitability—the hallmark of epilepsy—is accompanied by neuroinflammation and an excessive production of ROS; together, these factors are likely key features of seizure initiation and propagation. This review discusses the role of OS in epilepsy, its connection to neuroinflammation and the impact on synaptic function. Considering that the pharmacological treatment options for epilepsy are limited by the heterogeneity of these disorders, we also introduce the latest advances in anti-epileptic drugs (AEDs) and how they interact with OS. We conclude that OS is intertwined with numerous physiological and molecular mechanisms in epilepsy, although a causal relationship is yet to be established. Full article

(This article belongs to the Special Issue Oxidative Stress in Neurons)

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35 pages, 5983 KiB

Open AccessReview

The NRF2-Dependent Transcriptional Regulation of Antioxidant Defense Pathways: Relevance for Cell Type-Specific Vulnerability to Neurodegeneration and Therapeutic Intervention

by Stephanie M. Boas, Kathlene L. Joyce and Rita M. Cowell

Antioxidants 2022, 11(1), 8; https://doi.org/10.3390/antiox11010008 - 21 Dec 2021

Cited by 29 | Viewed by 5009

Abstract

Oxidative stress has been implicated in the etiology and pathobiology of various neurodegenerative diseases. At baseline, the cells of the nervous system have the capability to regulate the genes for antioxidant defenses by engaging nuclear factor erythroid 2 (NFE2/NRF)-dependent transcriptional mechanisms, and a [...] Read more.

Oxidative stress has been implicated in the etiology and pathobiology of various neurodegenerative diseases. At baseline, the cells of the nervous system have the capability to regulate the genes for antioxidant defenses by engaging nuclear factor erythroid 2 (NFE2/NRF)-dependent transcriptional mechanisms, and a number of strategies have been proposed to activate these pathways to promote neuroprotection. Here, we briefly review the biology of the transcription factors of the NFE2/NRF family in the brain and provide evidence for the differential cellular localization of NFE2/NRF family members in the cells of the nervous system. We then discuss these findings in the context of the oxidative stress observed in two neurodegenerative diseases, Parkinson’s disease (PD) and amyotrophic lateral sclerosis (ALS), and present current strategies for activating NFE2/NRF-dependent transcription. Based on the expression of the NFE2/NRF family members in restricted populations of neurons and glia, we propose that, when designing strategies to engage these pathways for neuroprotection, the relative contributions of neuronal and non-neuronal cell types to the overall oxidative state of tissue should be considered, as well as the cell types which have the greatest intrinsic capacity for producing antioxidant enzymes. Full article

(This article belongs to the Special Issue Oxidative Stress in Neurons)

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31 pages, 7120 KiB

Open AccessReview

Contribution of the Nrf2 Pathway on Oxidative Damage and Mitochondrial Failure in Parkinson and Alzheimer’s Disease

by Francisca Villavicencio Tejo and Rodrigo A Quintanilla

Antioxidants 2021, 10(7), 1069; https://doi.org/10.3390/antiox10071069 - 02 Jul 2021

Cited by 54 | Viewed by 13718

Abstract

The increase in human life expectancy has become a challenge to reduce the deleterious consequences of aging. Nowadays, an increasing number of the population suffer from age-associated neurodegenerative diseases including Parkinson’s disease (PD) and Alzheimer’s disease (AD). These disorders present different signs of [...] Read more.

The increase in human life expectancy has become a challenge to reduce the deleterious consequences of aging. Nowadays, an increasing number of the population suffer from age-associated neurodegenerative diseases including Parkinson’s disease (PD) and Alzheimer’s disease (AD). These disorders present different signs of neurodegeneration such as mitochondrial dysfunction, inflammation, and oxidative stress. Accumulative evidence suggests that the transcriptional factor nuclear factor (erythroid-derived 2)-like 2 (Nrf2) plays a vital defensive role orchestrating the antioxidant response in the brain. Nrf2 activation promotes the expression of several antioxidant enzymes that exert cytoprotective effects against oxidative damage and mitochondrial impairment. In this context, several studies have proposed a role of Nrf2 in the pathogenesis of PD and AD. Thus, we consider it important to summarize the ongoing literature related to the effects of the Nrf2 pathway in the context of these diseases. Therefore, in this review, we discuss the mechanisms involved in Nrf2 activity and its connection with mitochondria, energy supply, and antioxidant response in the brain. Furthermore, we will lead our discussion to identify the participation of the Nrf2 pathway in mitochondrial impairment and neurodegeneration present in PD and AD. Finally, we will discuss the therapeutic effects that the Nrf2 pathway activation could have on the cognitive impairment, neurodegeneration, and mitochondrial failure present in PD and AD. Full article

(This article belongs to the Special Issue Oxidative Stress in Neurons)

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19 pages, 834 KiB

Open AccessReview

Pituitary Adenylate Cyclase-Activating Polypeptide: A Potent Therapeutic Agent in Oxidative Stress

by Nadia Sadanandan, Blaise Cozene, You Jeong Park, Jeffrey Farooq, Chase Kingsbury, Zhen-Jie Wang, Alexa Moscatello, Madeline Saft, Justin Cho, Bella Gonzales-Portillo and Cesar V. Borlongan

Antioxidants 2021, 10(3), 354; https://doi.org/10.3390/antiox10030354 - 26 Feb 2021

Cited by 11 | Viewed by 3049

Abstract

Stroke is a life-threatening condition that is characterized by secondary cell death processes that occur after the initial disruption of blood flow to the brain. The inability of endogenous repair mechanisms to sufficiently support functional recovery in stroke patients and the inadequate treatment [...] Read more.

Stroke is a life-threatening condition that is characterized by secondary cell death processes that occur after the initial disruption of blood flow to the brain. The inability of endogenous repair mechanisms to sufficiently support functional recovery in stroke patients and the inadequate treatment options available are cause for concern. The pathology behind oxidative stress in stroke is of particular interest due to its detrimental effects on the brain. The oxidative stress caused by ischemic stroke overwhelms the neutralization capacity of the body’s endogenous antioxidant system, which leads to an overproduction of reactive oxygen species (ROS) and reactive nitrogen species (RNS) and eventually results in cell death. The overproduction of ROS compromises the functional and structural integrity of brain tissue. Therefore, it is essential to investigate the mechanisms involved in oxidative stress to help obtain adequate treatment options for stroke. Here, we focus on the latest preclinical research that details the mechanisms behind secondary cell death processes that cause many central nervous system (CNS) disorders, as well as research that relates to how the neuroprotective molecular mechanisms of pituitary adenylate cyclase-activating polypeptides (PACAPs) could make these molecules an ideal candidate for the treatment of stroke. Full article

(This article belongs to the Special Issue Oxidative Stress in Neurons)

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