scholarly journals NRF2 Activation Ameliorates Oxidative Stress and Improves Mitochondrial Function and Synaptic Plasticity, and in A53T α-Synuclein Hippocampal Neurons

Antioxidants ◽  
2021 ◽  
Vol 11 (1) ◽  
pp. 26
Author(s):  
Mikah S. Brandes ◽  
Jonathan A. Zweig ◽  
Anita Tang ◽  
Nora E. Gray
Keyword(s):  
Oxidative Stress ◽  
Synaptic Plasticity ◽  
Mitochondrial Function ◽  
Hippocampal Neurons ◽  
Neuronal Loss ◽  
Dimethyl Fumarate ◽  
Dendritic Arborization ◽  
Therapeutic Interventions ◽  
Spine Density ◽  
Nrf2 Activator

In Parkinson’s disease (PD), brain oxidative stress and mitochondrial dysfunction contribute to neuronal loss as well as motor and cognitive deficits. The transcription factor NRF2 has emerged as a promising therapeutic target in PD because it sits at the intersection of antioxidant and mitochondrial pathways. Here, we investigate the effects of modulating NRF2 activity in neurons isolated from a A53T α-synuclein (A53TSyn) mouse model of synucleinopathy. Embryonic hippocampal neurons were isolated from A53TSyn mice and their wild type (WT) littermates. Neurons were treated with either the NRF2 activator dimethyl fumarate (DMF) or the NRF2 inhibitor ML385. Reactive oxygen species (ROS), dendritic arborization and dendritic spine density were quantified. Mitochondrial bioenergetics were also profiled in these neurons. A53TSyn neurons had increased ROS and reduced basal and maximal mitochondrial respiration relative to WT neurons. A53TSyn neurons also displayed decreased dendritic arborization and reduced spine density. Treatment with DMF reduced ROS levels and improved both mitochondrial function and arborization, while inhibition of NRF2 with ML385 exacerbated these endpoints. Modulation of NRF2 activity had a significant effect on mitochondrial function, oxidative stress, and synaptic plasticity in A53TSyn neurons. These data suggest that NRF2 may be a viable target for therapeutic interventions in PD.

scholarly journals Centella asiatica Attenuates Mitochondrial Dysfunction and Oxidative Stress in Aβ-Exposed Hippocampal Neurons

2017 ◽  
Vol 2017 ◽  
pp. 1-8 ◽  
Author(s):  
Nora E. Gray ◽  
Jonathan A. Zweig ◽  
Donald G. Matthews ◽  
Maya Caruso ◽  
Joseph F. Quinn ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Mitochondrial Dysfunction ◽  
Mitochondrial Function ◽  
Hippocampal Neurons ◽  
Neuroblastoma Cells ◽  
Water Extract ◽  
Centella Asiatica ◽  
Antioxidant Response ◽  
And Oxidative Stress

Centella asiatica has been used for centuries to enhance memory. We have previously shown that a water extract of Centella asiatica (CAW) protects against the deleterious effects of amyloid-β (Aβ) in neuroblastoma cells and attenuates Aβ-induced cognitive deficits in mice. Yet, the neuroprotective mechanism of CAW has yet to be thoroughly explored in neurons from these animals. This study investigates the effects of CAW on neuronal metabolism and oxidative stress in isolated Aβ-expressing neurons. Hippocampal neurons from amyloid precursor protein overexpressing Tg2576 mice and wild-type (WT) littermates were treated with CAW. In both genotypes, CAW increased the expression of antioxidant response genes which attenuated the Aβ-induced elevations in reactive oxygen species (ROS) and lipid peroxidation in Tg2576 neurons. CAW also improved mitochondrial function in both genotypes and increased the expression of electron transport chain enzymes and mitochondrial labeling, suggesting an increase in mitochondrial content. These data show that CAW protects against mitochondrial dysfunction and oxidative stress in Aβ-exposed hippocampal neurons which could contribute to the beneficial effects of the extract observed in vivo. Since CAW also improved mitochondrial function in the absence of Aβ, these results suggest a broader utility for other conditions where neuronal mitochondrial dysfunction occurs.

Neuroprotective effect of Nrf2 activator dimethyl fumarate, on the hippocampal neurons in chemical kindling model in rat

2018 ◽  
Vol 143 ◽  
pp. 98-104 ◽  
Author(s):  
Neha Singh ◽  
Sheekha Vijayanti ◽  
Lekha Saha ◽  
Alka Bhatia ◽  
Dibyajyoti Banerjee ◽  
...  
Keyword(s):  
Hippocampal Neurons ◽  
Neuroprotective Effect ◽  
Dimethyl Fumarate ◽  
Kindling Model ◽  
Chemical Kindling ◽  
Nrf2 Activator

The Plastic and Functional Changes in Hippocampal Neurons during Preg nancy, Delivery and Postpartum Are Reversed by Offspring Deprivation

2020 ◽  
Vol 09 ◽  
Author(s):  
Maria C. Mostallino ◽  
Pietro P. Secci ◽  
Elena Paci ◽  
Maria L. Mura ◽  
Elisabetta Maciocco ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Synaptic Plasticity ◽  
Hippocampal Neurons ◽  
Trophic Factors ◽  
Spine Density ◽  
Sprague Dawley ◽  
Rapid Reduction ◽  
Plastic Properties ◽  
Functional Changes ◽  
Pregnancy And Lactation

Background: Pregnancy, and lactation are governed by hormones and neurophysiological processes, including differential expression of trophic factors, functional and structural synaptic plasticity and neurogenesis in different brain areas. Objectives: The aim of the study was to evaluate the amount of neurotrophic factors, synaptic plasticity and neurogenesis in the hippocampus of rats during pregnancy, lactation as well as in dams that were deprived from their pups one week af-ter birth or treated with Finasteride or Clomiphene. Methods: Adult female Sprague Dawley CD rats were treated with finasteride (25 mg/kg, subcutaneously) or clomiphene (5 mg/kg, intragastrically) from day 12 to 18 of pregnancy. Dams during pregnancy, lactation and those deprived from their pups which were sacrified 7 days after delivery were used to study Brain Derived Neurotrophic Factor (BDNF) and Activity-Regulated Cytoskeletal (Arc) protein expression, dendritic spine density (DSD), and cell proliferation in the hip-pocampus. Results: BDNF, Arc and DSD markedly increased after 21 days of pregnancy (the time of delivery), an effect that lasted for 21 days during lactation and was abolished by physiological weaning (21 days after delivery). The modifications in the mentioned parameters were associated with a dramatic reduction of neurosteroid content when compared to estrus fe-males. In contrast, after 21 days of pregnancy we observed an increase in cell proliferation and a decrease during the first three weeks of postpartum. Finasteride and clomifene failed to modify the changes in BDNF and Arc content elicited by pregnancy and delivery. Pups deprivation induced a rapid reduction in the amount of BDNF, Arc and DSD while increas-ing cell proliferation. Conclusion: In rats, the changes in plastic properties of hippocampal neurons during pregnancy, lactation and pups depri-vation may play a crucial role in the modulation of maternal care.

Rapid Effects of Estradiol on Dendritic Spines and Synaptic Plasticity in the Male and Female Hippocampus

2020 ◽  
pp. 38-47
Author(s):  
Asami Kato ◽  
Gen Murakami ◽  
Yasushi Hojo ◽  
Sigeo Horie ◽  
Suguru Kawato
Keyword(s):  
Synaptic Plasticity ◽  
Dendritic Spine ◽  
Hippocampal Neurons ◽  
Molecular Mechanisms ◽  
Hippocampal Slices ◽  
Spine Density ◽  
Male And Female ◽  
Dendritic Spine Density ◽  
Male And Female Rats ◽  
Rapid Modulation

Although the potent estrogen, 17β‎-estradiol (E2), has long been known to regulate the hippocampal dendritic spine density and synaptic plasticity, the molecular mechanisms through which it does so are less well understood. This chapter discusses the rapid modulation of hippocampal dendritic spine density and synaptic plasticity in male and female rats, with particular attention to studies in hippocampal slices from male rats. Among the mechanisms described are the roles of specific cell-signaling kinases and estrogen receptors in mediating the effects of E2 and progesterone on hippocampal neurons. In addition, dynamic changes of spine structures over time and sex differences in spine regulation are also considered. Finally, the chapter ends by discussing the importance of local hippocampal synthesis of E2 and androgens to hippocampal spine morphology and plasticity.

scholarly journals Control of Oxidative Stress and Inflammation in Sickle Cell Disease with the Nrf2 Activator Dimethyl Fumarate

2017 ◽  
Vol 26 (14) ◽  
pp. 748-762 ◽  
Author(s):  
John D. Belcher ◽  
Chunsheng Chen ◽  
Julia Nguyen ◽  
Ping Zhang ◽  
Fuad Abdulla ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Dimethyl Fumarate ◽  
Cell Disease ◽  
Nrf2 Activator

Antidepressant effects of acupoint stimulation and fluoxetine by increasing dendritic arborization and spine density in CA1 hippocampal neurons of socially isolated rats

2018 ◽  
Vol 675 ◽  
pp. 48-53 ◽  
Author(s):  
Amalia Dávila-Hernández ◽  
Sergio R. Zamudio ◽  
Lucía Martínez-Mota ◽  
Roberto González-González ◽  
Eduardo Ramírez-San Juan
Keyword(s):  
Hippocampal Neurons ◽  
Dendritic Arborization ◽  
Spine Density ◽  
Antidepressant Effects ◽  
Socially Isolated ◽  
Acupoint Stimulation

scholarly journals Electrophiles against (Skin) Diseases: More Than Nrf2

Biomolecules ◽  
2020 ◽  
Vol 10 (2) ◽  
pp. 271 ◽  
Author(s):  
Paulina Hennig ◽  
Gabriele Fenini ◽  
Michela Di Filippo ◽  
Hans-Dietmar Beer
Keyword(s):  
Oxidative Stress ◽  
Transcription Factor ◽  
Molecular Mechanisms ◽  
Skin Diseases ◽  
Inflammatory Diseases ◽  
Protein Complexes ◽  
Dimethyl Fumarate ◽  
Inflammatory Conditions ◽  
Nrf2 Activation ◽  
Nrf2 Activator

The skin represents an indispensable barrier between the organism and the environment and is the first line of defense against exogenous insults. The transcription factor NRF2 is a central regulator of cytoprotection and stress resistance. NRF2 is activated in response to oxidative stress by reactive oxygen species (ROS) and electrophiles. These electrophiles oxidize specific cysteine residues of the NRF2 inhibitor KEAP1, leading to KEAP1 inactivation and, subsequently, NRF2 activation. As oxidative stress is associated with inflammation, the NRF2 pathway plays important roles in the pathogenesis of common inflammatory diseases and cancer in many tissues and organs, including the skin. The electrophile and NRF2 activator dimethyl fumarate (DMF) is an established and efficient drug for patients suffering from the common inflammatory skin disease psoriasis and the neuro-inflammatory disease multiple sclerosis (MS). In this review, we discuss possible molecular mechanisms underlying the therapeutic activity of DMF and other NRF2 activators. Recent evidence suggests that electrophiles not only activate NRF2, but also target other inflammation-associated pathways including the transcription factor NF-κB and the multi-protein complexes termed inflammasomes. Inflammasomes are central regulators of inflammation and are involved in many inflammatory conditions. Most importantly, the NRF2 and inflammasome pathways are connected at different levels, mainly antagonistically.

l-Serine dietary supplementation is associated with clinical improvement of loss-of-function GRIN2B-related pediatric encephalopathy

2019 ◽  
Vol 12 (586) ◽  
pp. eaaw0936 ◽  
Author(s):  
David Soto ◽  
Mireia Olivella ◽  
Cristina Grau ◽  
Judith Armstrong ◽  
Clara Alcon ◽  
...  
Keyword(s):  
Hippocampal Neurons ◽  
De Novo ◽  
Dietary Supplementation ◽  
293T Cell ◽  
Therapeutic Interventions ◽  
Spine Density ◽  
Loss Of Function ◽  
De Novo Mutations ◽  
Electrophysiological Recordings ◽  
Neurological Conditions

Autosomal dominant mutations in GRIN2B are associated with severe encephalopathy, but little is known about the pathophysiological outcomes and any potential therapeutic interventions. Genetic studies have described the association between de novo mutations of genes encoding the subunits of the N-methyl-d-aspartate receptor (NMDAR) and severe neurological conditions. Here, we evaluated a missense mutation in GRIN2B, causing a proline-to-threonine switch (P553T) in the GluN2B subunit of NMDAR, which was found in a 5-year-old patient with Rett-like syndrome with severe encephalopathy. Structural molecular modeling predicted a reduced pore size of the mutant GluN2B-containing NMDARs. Electrophysiological recordings in a HEK-293T cell line expressing the mutated subunit confirmed this prediction and showed an associated reduced glutamate affinity. Moreover, GluN2B(P553T)-expressing primary murine hippocampal neurons showed decreased spine density, concomitant with reduced NMDA-evoked currents and impaired NMDAR-dependent insertion of the AMPA receptor subunit GluA1 at stimulated synapses. Furthermore, the naturally occurring coagonist d-serine restored function to GluN2B(P553T)-containing NMDARs. l-Serine dietary supplementation of the patient was hence initiated, resulting in the increased abundance of d-serine in the plasma and brain. The patient has shown notable improvements in motor and cognitive performance and communication after 11 and 17 months of l-serine dietary supplementation. Our data suggest that l-serine supplementation might ameliorate GRIN2B-related severe encephalopathy and other neurological conditions caused by glutamatergic signaling deficiency.

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