18 results on '"Baxter, Paul S."'
Search Results
2. Targeted de-repression of neuronal Nrf2 inhibits α-synuclein accumulation
- Author
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Baxter, Paul S., Márkus, Nóra M., Dando, Owen, He, Xin, Al-Mubarak, Bashayer R., Qiu, Jing, and Hardingham, Giles E.
- Published
- 2021
- Full Text
- View/download PDF
3. Mixed-species RNA-seq for elucidation of non-cell-autonomous control of gene transcription
- Author
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Qiu, Jing, Dando, Owen, Baxter, Paul S., Hasel, Philip, Heron, Samuel, Simpson, T. Ian, and Hardingham, Giles E.
- Published
- 2018
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4. Differential splicing choices made by neurons and astrocytes and their importance when investigating signal-dependent alternative splicing in neural cells.
- Author
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Baxter, Paul S., Dando, Owen, and Hardingham, Giles E.
- Subjects
ALTERNATIVE RNA splicing ,ION channels ,NEURAL stem cells ,CELL adhesion ,CELL adhesion molecules ,NEUROTRANSMITTER receptors ,NEURONS ,ASTROCYTES ,CELL receptors - Abstract
A variety of proteins can be encoded by a single gene via the differential splicing of exons. In neurons this form of alternative splicing can be controlled by activitydependent calcium signaling, leading to the properties of proteins being altered, including ion channels, neurotransmitter receptors and synaptic cell adhesion molecules. The pre-synaptic cell adhesion molecule Neurexin 1 (Nrxn1) is alternatively spliced at splice-site 4 (SS4) which governs exon 22 inclusion (SS4+) and consequently postsynaptic NMDA receptor responses. Nrxn1 was reported to be subject to a delayed-onset shift in Nrxn1 SS4 splicing resulting in increased exon 22 inclusion, involving epigenetic mechanisms which, if disrupted, reduce memory stability. Exon inclusion at SS4 represented one of hundreds of exons reported to be subject to a genome-wide shift in fractional exon inclusion following membrane depolarization with high extracellular K+ that was delayed in onset. We report that high K+ does not increase the SS4+/SS4 ratio in cortical neurons, but does induce a delayed-onset NMDA receptor-dependent neuronal death. In mixed neuronal/astrocyte cultures this neuronal death results in an increase in the astrocyte: neuron ratio, and a misleading increase in SS4+/SS4 ratio attributable to astrocytes having a far higher SS4+/SS4 ratio than neurons, rather than any change in the neurons themselves. We reassessed the previously reported genome-wide delayed-onset shift in fractional exon inclusion after high K+ exposure. This revealed that the reported changes correlated strongly with differences in exon inclusion level between astrocytes and neurons, and was accompanied by a strong decrease in the ratio of neuron-specific: astrocytespecific gene expression. As such, these changes can be explained by the neurotoxic nature of the stimulation paradigm, underlining the importance of NMDA receptor blockade when using high K+ depolarizing stimuli. [ABSTRACT FROM AUTHOR]
- Published
- 2023
- Full Text
- View/download PDF
5. Ultrasound of Abdominal Transplantation
- Author
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Paul S. Sidhu, Grant M. Baxter, Paul S. Sidhu, Grant M. Baxter and Paul S. Sidhu, Grant M. Baxter, Paul S. Sidhu, Grant M. Baxter
- Published
- 2011
6. Ultrasound of the Urogenital System
- Author
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Grant M. Baxter, Paul S. Sidhu and Grant M. Baxter, Paul S. Sidhu
- Published
- 2006
7. Imbalance of flight–freeze responses and their cellular correlates in the Nlgn3−/y rat model of autism.
- Author
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Anstey, Natasha J., Kapgal, Vijayakumar, Tiwari, Shashank, Watson, Thomas C., Toft, Anna K. H., Dando, Owen R., Inkpen, Felicity H., Baxter, Paul S., Kozić, Zrinko, Jackson, Adam D., He, Xin, Nawaz, Mohammad Sarfaraz, Kayenaat, Aiman, Bhattacharya, Aditi, Wyllie, David J. A., Chattarji, Sumantra, Wood, Emma R., Hardt, Oliver, and Kind, Peter C.
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ANIMAL disease models ,AUTISM spectrum disorders ,NEURAL transmission ,AUTISM ,ELECTRIC stimulation ,INTELLECTUAL disabilities - Abstract
Background: Mutations in the postsynaptic transmembrane protein neuroligin-3 are highly correlative with autism spectrum disorders (ASDs) and intellectual disabilities (IDs). Fear learning is well studied in models of these disorders, however differences in fear response behaviours are often overlooked. We aim to examine fear behaviour and its cellular underpinnings in a rat model of ASD/ID lacking Nlgn3. Methods: This study uses a range of behavioural tests to understand differences in fear response behaviour in Nlgn3
−/y rats. Following this, we examined the physiological underpinnings of this in neurons of the periaqueductal grey (PAG), a midbrain area involved in flight-or-freeze responses. We used whole-cell patch-clamp recordings from ex vivo PAG slices, in addition to in vivo local-field potential recordings and electrical stimulation of the PAG in wildtype and Nlgn3−/y rats. We analysed behavioural data with two- and three-way ANOVAS and electrophysiological data with generalised linear mixed modelling (GLMM). Results: We observed that, unlike the wildtype, Nlgn3−/y rats are more likely to response with flight rather than freezing in threatening situations. Electrophysiological findings were in agreement with these behavioural outcomes. We found in ex vivo slices from Nlgn3−/y rats that neurons in dorsal PAG (dPAG) showed intrinsic hyperexcitability compared to wildtype. Similarly, stimulating dPAG in vivo revealed that lower magnitudes sufficed to evoke flight behaviour in Nlgn3−/y than wildtype rats, indicating the functional impact of the increased cellular excitability. Limitations: Our findings do not examine what specific cell type in the PAG is likely responsible for these phenotypes. Furthermore, we have focussed on phenotypes in young adult animals, whilst the human condition associated with NLGN3 mutations appears during the first few years of life. Conclusions: We describe altered fear responses in Nlgn3−/y rats and provide evidence that this is the result of a circuit bias that predisposes flight over freeze responses. Additionally, we demonstrate the first link between PAG dysfunction and ASD/ID. This study provides new insight into potential pathophysiologies leading to anxiety disorders and changes to fear responses in individuals with ASD. [ABSTRACT FROM AUTHOR]- Published
- 2022
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8. The Developmental Shift of NMDA Receptor Composition Proceeds Independently of GluN2 Subunit-Specific GluN2 C-Terminal Sequences
- Author
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McKay, Sean, Ryan, Tomás J., McQueen, Jamie, Indersmitten, Tim, Marwick, Katie F.M., Hasel, Philip, Kopanitsa, Maksym V., Baxter, Paul S., Martel, Marc-André, Kind, Peter C., Wyllie, David J.A., O’Dell, Thomas J., Grant, Seth G.N., Hardingham, Giles E., and Komiyama, Noboru H.
- Subjects
synaptogenesis ,synaptic plasticity ,Binding Sites ,neurodevelopment ,musculoskeletal, neural, and ocular physiology ,Neurogenesis ,Long-Term Potentiation ,NMDA receptor ,Receptors, N-Methyl-D-Aspartate ,Article ,Rats ,Mice, Inbred C57BL ,Protein Subunits ,nervous system ,lcsh:Biology (General) ,Mutation ,Synapses ,Animals ,Amino Acid Sequence ,Phosphorylation ,Theta Rhythm ,Calcium-Calmodulin-Dependent Protein Kinase Type 2 ,lcsh:QH301-705.5 - Abstract
Summary The GluN2 subtype (2A versus 2B) determines biophysical properties and signaling of forebrain NMDA receptors (NMDARs). During development, GluN2A becomes incorporated into previously GluN2B-dominated NMDARs. This “switch” is proposed to be driven by distinct features of GluN2 cytoplasmic C-terminal domains (CTDs), including a unique CaMKII interaction site in GluN2B that drives removal from the synapse. However, these models remain untested in the context of endogenous NMDARs. We show that, although mutating the endogenous GluN2B CaMKII site has secondary effects on GluN2B CTD phosphorylation, the developmental changes in NMDAR composition occur normally and measures of plasticity and synaptogenesis are unaffected. Moreover, the switch proceeds normally in mice that have the GluN2A CTD replaced by that of GluN2B and commences without an observable decline in GluN2B levels but is impaired by GluN2A haploinsufficiency. Thus, GluN2A expression levels, and not GluN2 subtype-specific CTD-driven events, are the overriding factor in the developmental switch in NMDAR composition., Graphical Abstract, Highlights • Mutating the GluN2B CaMKII site affects phosphorylation of its C-terminal domain • The developmental changes in NMDAR composition and synaptogenesis occur normally • Changes in NMDAR composition do not require distinct GluN2 C-terminal domains • Developmental changes in NMDAR composition are primarily sensitive to GluN2A levels, An important milestone in forebrain neuronal development is the switch in composition of the NMDA receptor: GluN2A becomes incorporated into previously GluN2B-dominated NMDARs. Using knockin mice, McKay et al. find that, contrary to earlier proposed models, the switch does not require GluN2A and GluN2B to possess distinct C-terminal domain sequences.
- Published
- 2018
9. Pituitary adenylate cyclase-activating peptide induces long-lasting neuroprotection through the induction of activity-dependent signaling via the cyclic AMP response element-binding protein-regulated transcription co-activator 1
- Author
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Baxter, Paul S., Martel, Marc-Andre, McMahon, Aoife, Kind, Peter C., and Hardingham, Giles E.
- Published
- 2011
- Full Text
- View/download PDF
10. Adaptive regulation of the brain’s antioxidant defences by neurons and astrocytes
- Author
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Baxter, Paul S. and Hardingham, Giles E.
- Subjects
Neurons ,NF-E2-Related Factor 2 ,Brain ,Review Article ,Biochemistry ,Antioxidants ,Mitochondria ,nervous system ,Physiology (medical) ,Astrocytes ,Animals ,Humans ,Reactive Oxygen Species ,Oxidation-Reduction ,Signal Transduction - Abstract
The human brain generally remains structurally and functionally sound for many decades, despite the post-mitotic and non-regenerative nature of neurons. This is testament to the brain’s profound capacity for homeostasis: both neurons and glia have in-built mechanisms that enable them to mount adaptive or protective responses to potentially challenging situations, ensuring that cellular viability and functionality is maintained. The high and variable metabolic and mitochondrial activity of neurons places several demands on the brain, including the task of neutralizing the associated reactive oxygen species (ROS) produced, to limit the accumulation of oxidative damage. Astrocytes play a key role in providing antioxidant support to nearby neurons, and redox regulation of the astrocytic Nrf2 pathway represents a powerful homeostatic regulator of the large cohort of Nrf2-regulated antioxidant genes that they express. In contrast, the Nrf2 pathway is weak in neurons, robbing them of this particular homeostatic device. However, many neuronal antioxidant genes are controlled by synaptic activity, enabling activity-dependent increases in ROS production to be offset by enhanced antioxidant capacity of both glutathione and thioredoxin-peroxiredoxin systems. These distinct homeostatic mechanisms in neurons and astrocytes together combine to promote neuronal resistance to oxidative insults. Future investigations into signaling between distinct cell types within the neuro-glial unit are likely to uncover further mechanisms underlying redox homeostasis in the brain., Highlights • Redox homeostasis is essential for brain health. • Homeostasis involves interactions within the neurogliovascular unit. • We describe cooperative contributions by neurons and astrocytes to redox homeostasis.
- Published
- 2016
11. Adaptive regulation of the brain's antioxidant defences by neurons and astrocytes
- Author
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Baxter, Paul S and Hardingham, Giles E
- Subjects
nervous system - Abstract
The human brain generally remains structurally and functionally sound for many decades, despite the post-mitotic and non-regenerative nature of neurons. This is testament to the brain's profound capacity for homeostasis: both neurons and glia have in-built mechanisms that enable them to mount adaptive or protective responses to potentially challenging situations, ensuring that cellular viability and functionality is maintained. The high and variable metabolic and mitochondrial activity of neurons places several demands on the brain, including the task of neutralizing the associated reactive oxygen species (ROS) produced, to limit the accumulation of oxidative damage. Astrocytes play a key role in providing antioxidant support to nearby neurons, and redox regulation of the astrocytic Nrf2 pathway represents a powerful homeostatic regulator of the large cohort of Nrf2-regulated antioxidant genes that they express. In contrast, the Nrf2 pathway is weak in neurons, robbing them of this particular homeostatic device. However, many neuronal antioxidant genes are controlled by synaptic activity, enabling activity-dependent increases in ROS production to be offset by enhanced antioxidant capacity of both glutathione and thioredoxin-peroxiredoxin systems. These distinct homeostatic mechanisms in neurons and astrocytes together combine to promote neuronal resistance to oxidative insults. Future investigations into signaling between distinct cell types within the neuro-glial unit are likely to uncover further mechanisms underlying redox homeostasis in the brain.
- Published
- 2016
12. Synaptic NMDA receptor activity is coupled to the transcriptional control of the glutathione system
- Author
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Baxter, Paul S., Bell, Karen F S, Hasel, Philip, Kaindl, Angela M., Fricker, Michael, Thomson, Derek, Cregan, Sean P., Gillingwater, Thomas H., and Hardingham, Giles E.
- Subjects
nervous system - Abstract
How the brain's antioxidant defenses adapt to changing demand is incompletely understood. Here we show that synaptic activity is coupled, via the NMDA receptor (NMDAR), to control of the glutathione antioxidant system. This tunes antioxidant capacity to reflect the elevated needs of an active neuron, guards against future increased demand and maintains redox balance in the brain. This control is mediated via a programme of gene expression changes that boosts the synthesis, recycling and utilization of glutathione, facilitating ROS detoxification and preventing Puma-dependent neuronal apoptosis. Of particular importance to the developing brain is the direct NMDAR-dependent transcriptional control of glutathione biosynthesis, disruption of which can lead to degeneration. Notably, these activity-dependent cell-autonomous mechanisms were found to cooperate with non-cell-autonomous Nrf2-driven support from astrocytes to maintain neuronal GSH levels in the face of oxidative insults. Thus, developmental NMDAR hypofunction and glutathione system deficits, separately implicated in several neurodevelopmental disorders, are mechanistically linked.
- Published
- 2015
13. Microglial identity and inflammatory responses are controlled by the combined effects of neurons and astrocytes.
- Author
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Baxter, Paul S., Dando, Owen, Emelianova, Katie, He, Xin, McKay, Sean, Hardingham, Giles E., and Qiu, Jing
- Abstract
Microglia, brain-resident macrophages, require instruction from the CNS microenvironment to maintain their identity and morphology and regulate inflammatory responses, although what mediates this is unclear. Here, we show that neurons and astrocytes cooperate to promote microglial ramification, induce expression of microglial signature genes ordinarily lost in vitro and in age and disease in vivo , and repress infection- and injury-associated gene sets. The influence of neurons and astrocytes separately on microglia is weak, indicative of synergies between these cell types, which exert their effects via a mechanism involving transforming growth factor β2 (TGF-β2) signaling. Neurons and astrocytes also combine to provide immunomodulatory cues, repressing primed microglial responses to weak inflammatory stimuli (without affecting maximal responses) and consequently limiting the feedback effects of inflammation on the neurons and astrocytes themselves. These findings explain why microglia isolated ex vivo undergo de-differentiation and inflammatory deregulation and point to how disease- and age-associated changes may be counteracted. [Display omitted] • Neurons and astrocytes combine to promote the microglial homeostatic signature • This rescues changes that happen in microglia ex vivo and in disease • Mechanistically, this involves transforming growth factor beta 2 (TBGF-β2) signaling • Neurons and astrocytes also repress microglial inflammatory responses Baxter et al. show that the transformation of microglia from a healthy to disease-associated state can be suppressed by the combined actions of neurons and astrocytes via a mechanism involving TBGF-β2 signaling. They also repress exaggerated microglial responses to mild stimuli and limit the feedback signaling from activated microglia. [ABSTRACT FROM AUTHOR]
- Published
- 2021
- Full Text
- View/download PDF
14. Corrigendum: Synaptic NMDA receptor activity is coupled to the transcriptional control of the glutathione system.
- Author
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Baxter, Paul S., Bell, Karen F. S., Hasel, Philip, Kaindl, Angela M., Fricker, Michael, Thomson, Derek., Cregan, Sean P., Gillingwater, Thomas H., and Hardingham, Giles E.
- Abstract
This corrects the article DOI: 10.1038/ncomms7761 [ABSTRACT FROM AUTHOR]
- Published
- 2017
- Full Text
- View/download PDF
15. Non-canonical Keap1-independent activation of Nrf2 in astrocytes by mild oxidative stress.
- Author
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Al-Mubarak BR, Bell KFS, Chowdhry S, Meakin PJ, Baxter PS, McKay S, Dando O, Ashford MLJ, Gazaryan I, Hayes JD, and Hardingham GE
- Subjects
- Animals, Antioxidants, Kelch-Like ECH-Associated Protein 1 genetics, Mice, NF-E2-Related Factor 2 genetics, Oxidative Stress, Astrocytes metabolism, Kelch-Like ECH-Associated Protein 1 metabolism, NF-E2-Related Factor 2 metabolism
- Abstract
The transcription factor Nrf2 is a stress-responsive master regulator of antioxidant, detoxification and proteostasis genes. In astrocytes, Nrf2-dependent gene expression drives cell-autonomous cytoprotection and also non-cell-autonomous protection of nearby neurons, and can ameliorate pathology in several acute and chronic neurological disorders associated with oxidative stress. However, the value of astrocytic Nrf2 as a therapeutic target depends in part on whether Nrf2 activation by disease-associated oxidative stress occludes the effect of any Nrf2-activating drug. Nrf2 activation classically involves the inhibition of interactions between Nrf2's Neh2 domain and Keap1, which directs Nrf2 degradation. Keap1 inhibition is mediated by the modification of cysteine residues on Keap1, and can be triggered by electrophilic small molecules such as tBHQ. Here we show that astrocytic Nrf2 activation by oxidative stress involves Keap1-independent non-canonical signaling. Keap1 deficiency elevates basal Nrf2 target gene expression in astrocytes and occludes the effects of tBHQ, oxidative stress still induced strong Nrf2-dependent gene expression in Keap1-deficient astrocytes. Moreover, while tBHQ prevented protein degradation mediated via Nrf2's Neh2 domain, oxidative stress did not, consistent with a Keap1-independent mechanism. Moreover the effects of oxidative stress and tBHQ on Nrf2 target gene expression are additive, not occlusive. Mechanistically, oxidative stress enhances the transactivation potential of Nrf2's Neh5 domain in a manner dependent on its Cys-191 residue. Thus, astrocytic Nrf2 activation by oxidative stress involves Keap1-independent non-canonical signaling, meaning that further Nrf2 activation by Keap1-inhibiting drugs may be a viable therapeutic strategy., (Copyright © 2021. Published by Elsevier B.V.)
- Published
- 2021
- Full Text
- View/download PDF
16. Input-Output Relationship of CA1 Pyramidal Neurons Reveals Intact Homeostatic Mechanisms in a Mouse Model of Fragile X Syndrome.
- Author
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Booker SA, Simões de Oliveira L, Anstey NJ, Kozic Z, Dando OR, Jackson AD, Baxter PS, Isom LL, Sherman DL, Hardingham GE, Brophy PJ, Wyllie DJA, and Kind PC
- Subjects
- Animals, Disease Models, Animal, Homeostasis, Mice, Fragile X Syndrome genetics, Pyramidal Cells metabolism
- Abstract
Cellular hyperexcitability is a salient feature of fragile X syndrome animal models. The cellular basis of hyperexcitability and how it responds to changing activity states is not fully understood. Here, we show increased axon initial segment length in CA1 of the Fmr1
-/y mouse hippocampus, with increased cellular excitability. This change in length does not result from reduced AIS plasticity, as prolonged depolarization induces changes in AIS length independent of genotype. However, depolarization does reduce cellular excitability, the magnitude of which is greater in Fmr1-/y neurons. Finally, we observe reduced functional inputs from the entorhinal cortex, with no genotypic difference in the firing rates of CA1 pyramidal neurons. This suggests that AIS-dependent hyperexcitability in Fmr1-/y mice may result from adaptive or homeostatic regulation induced by reduced functional synaptic connectivity. Thus, while AIS length and intrinsic excitability contribute to cellular hyperexcitability, they may reflect a homeostatic mechanism for reduced synaptic input onto CA1 neurons., Competing Interests: Declaration of Interests The authors declare no competing interests., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)- Published
- 2020
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- View/download PDF
17. Synaptic NMDA receptor activity is coupled to the transcriptional control of the glutathione system.
- Author
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Baxter PS, Bell KF, Hasel P, Kaindl AM, Fricker M, Thomson D, Cregan SP, Gillingwater TH, and Hardingham GE
- Subjects
- Animals, Apoptosis drug effects, Apoptosis Regulatory Proteins genetics, Astrocytes drug effects, Astrocytes metabolism, Cells, Cultured, Cerebral Cortex cytology, Dizocilpine Maleate pharmacology, Electrical Synapses drug effects, Excitatory Amino Acid Antagonists pharmacology, Frontal Lobe drug effects, Gene Expression Regulation, Glutathione drug effects, Glutathione Peroxidase drug effects, Glutathione Transferase drug effects, Mice, Mice, Knockout, NF-E2-Related Factor 2 drug effects, NF-E2-Related Factor 2 metabolism, Neurons drug effects, Rats, Rats, Sprague-Dawley, Reactive Oxygen Species metabolism, Receptors, N-Methyl-D-Aspartate antagonists & inhibitors, Transcription, Genetic drug effects, Tumor Suppressor Proteins genetics, Electrical Synapses metabolism, Frontal Lobe metabolism, Glutathione metabolism, Glutathione Peroxidase metabolism, Glutathione Transferase metabolism, Neurons metabolism, Receptors, N-Methyl-D-Aspartate metabolism
- Abstract
How the brain's antioxidant defenses adapt to changing demand is incompletely understood. Here we show that synaptic activity is coupled, via the NMDA receptor (NMDAR), to control of the glutathione antioxidant system. This tunes antioxidant capacity to reflect the elevated needs of an active neuron, guards against future increased demand and maintains redox balance in the brain. This control is mediated via a programme of gene expression changes that boosts the synthesis, recycling and utilization of glutathione, facilitating ROS detoxification and preventing Puma-dependent neuronal apoptosis. Of particular importance to the developing brain is the direct NMDAR-dependent transcriptional control of glutathione biosynthesis, disruption of which can lead to degeneration. Notably, these activity-dependent cell-autonomous mechanisms were found to cooperate with non-cell-autonomous Nrf2-driven support from astrocytes to maintain neuronal GSH levels in the face of oxidative insults. Thus, developmental NMDAR hypofunction and glutathione system deficits, separately implicated in several neurodevelopmental disorders, are mechanistically linked.
- Published
- 2015
- Full Text
- View/download PDF
18. Mild oxidative stress activates Nrf2 in astrocytes, which contributes to neuroprotective ischemic preconditioning.
- Author
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Bell KF, Al-Mubarak B, Fowler JH, Baxter PS, Gupta K, Tsujita T, Chowdhry S, Patani R, Chandran S, Horsburgh K, Hayes JD, and Hardingham GE
- Subjects
- Animals, Cells, Cultured, Gene Expression Regulation, Enzymologic drug effects, Heme Oxygenase (Decyclizing) metabolism, Hydrogen Peroxide pharmacology, Ischemic Preconditioning, Oxidoreductases Acting on Sulfur Group Donors metabolism, Rats, Astrocytes metabolism, Gene Expression Regulation, Enzymologic physiology, NF-E2-Related Factor 2 metabolism, Neurons metabolism, Neuroprotective Agents metabolism, Oxidative Stress physiology
- Published
- 2011
- Full Text
- View/download PDF
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