scholarly journals Glutathione in the Brain

2021 ◽  
Vol 22 (9) ◽  
pp. 5010
Author(s):  
Koji Aoyama
Keyword(s):  
Neurodegenerative Diseases ◽  
Regulatory Mechanism ◽  
Excitatory Amino Acid ◽  
Redox Homeostasis ◽  
Disease Onset ◽  
Glutamate Transporter ◽  
Antioxidant Defense System ◽  
Common Finding ◽  
Potential Therapeutic Application ◽  
The Brain

Glutathione (GSH) is the most abundant non-protein thiol, and plays crucial roles in the antioxidant defense system and the maintenance of redox homeostasis in neurons. GSH depletion in the brain is a common finding in patients with neurodegenerative diseases, such as Alzheimer’s disease and Parkinson’s disease, and can cause neurodegeneration prior to disease onset. Excitatory amino acid carrier 1 (EAAC1), a sodium-dependent glutamate/cysteine transporter that is selectively present in neurons, plays a central role in the regulation of neuronal GSH production. The expression of EAAC1 is posttranslationally controlled by the glutamate transporter-associated protein 3–18 (GTRAP3-18) or miR-96-5p in neurons. The regulatory mechanism of neuronal GSH production mediated by EAAC1 may be a new target in therapeutic strategies for these neurodegenerative diseases. This review describes the regulatory mechanism of neuronal GSH production and its potential therapeutic application in the treatment of neurodegenerative diseases.

scholarly journals Redox Homeostasis and Prospects for Therapeutic Targeting in Neurodegenerative Disorders

2021 ◽  
Vol 2021 ◽  
pp. 1-14
Author(s):  
Musbau Adewumi Akanji ◽  
Damilare Emmanuel Rotimi ◽  
Tobiloba Christiana Elebiyo ◽  
Oluwakemi Josephine Awakan ◽  
Oluyomi Stephen Adeyemi
Keyword(s):  
Neurodegenerative Diseases ◽  
Neurodegenerative Disorders ◽  
Redox Homeostasis ◽  
Reactive Species ◽  
Cellular Damage ◽  
Cellular Mechanisms ◽  
Cellular Redox ◽  
Redox Imbalance ◽  
Cellular Processes ◽  
The Brain

Reactive species, such as those of oxygen, nitrogen, and sulfur, are considered part of normal cellular metabolism and play significant roles that can impact several signaling processes in ways that lead to either cellular sustenance, protection, or damage. Cellular redox processes involve a balance in the production of reactive species (RS) and their removal because redox imbalance may facilitate oxidative damage. Physiologically, redox homeostasis is essential for the maintenance of many cellular processes. RS may serve as signaling molecules or cause oxidative cellular damage depending on the delicate equilibrium between RS production and their efficient removal through the use of enzymatic or nonenzymatic cellular mechanisms. Moreover, accumulating evidence suggests that redox imbalance plays a significant role in the progression of several neurodegenerative diseases. For example, studies have shown that redox imbalance in the brain mediates neurodegeneration and alters normal cytoprotective responses to stress. Therefore, this review describes redox homeostasis in neurodegenerative diseases with a focus on Alzheimer’s and Parkinson’s disease. A clearer understanding of the redox-regulated processes in neurodegenerative disorders may afford opportunities for newer therapeutic strategies.

scholarly journals Neuroprotective Effects of Magnesium L-threonate in a Hypoxic Zebrafish Model

2020 ◽  
Author(s):  
Young Sung Kim ◽  
Young Ju Won ◽  
Byung Gun Lim ◽  
Too Jae Min ◽  
Yeon-Hwa Kim ◽  
...  
Keyword(s):  
Cognitive Function ◽  
Cerebral Infarction ◽  
Cell Viability ◽  
Excitatory Amino Acid ◽  
Glutamate Transporter ◽  
Protective Effects ◽  
Triphenyltetrazolium Chloride ◽  
Zebrafish Model ◽  
Neuroprotective Effects ◽  
The Brain

Abstract Background: Hypoxia inhibits the uptake of glutamate (a major neurotransmitter in the brain closely related to cognitive function) into brain cells, and the initial response of cells to cortical hypoxia depends on glutamate. Previous studies have suggested that magnesium may have protective effects against hypoxic injuries. In particular, magnesium L-threonate (MgT) may increase magnesium ion concentrations in the brain better than MgSO4 and improve cognitive function. Methods: We evaluated cell viability under hypoxic conditions in the MgT- and MgSO4-treated human SH-SY5Y neurons, in vivo behavior using the T-maze test following hypoxia in MgT-treated zebrafish, activity of brain mitochondrial dehydrogenase by 2,3,5-triphenyltetrazolium chloride (TTC) staining, and protein expression of the excitatory amino acid transporter (EAAT) 4 glutamate transporter by western blotting. Results: Among the groups treated with hypoxia, cell viability significantly increased when pre-treated with 1 or 10 mM MgT (p = 0.009 and 0.026, respectively) Despite hypoxic insult, MgT-treated zebrafish showed preferences for the red compartment (p= 0.025 for distance and p= 0.007 for frequency of entries), suggesting memory preservation. TTC staining showed reduced cerebral infarction and preserved absorbance in the MgT-treated zebrafish brain after hypoxia (p=0.010 compared to the hypoxia group). In addition, western blot showed upregulation of EAAT4 protein in the MgT treated group. Conclusions: Pre-treatment with MgT attenuated cell death and cerebral infarction due to hypoxia and protected cognitive function in zebrafish. In addition, MgT appeared to modulate expression of the glutamate transporter, EAAT4.

scholarly journals Intersection between Redox Homeostasis and Autophagy: Valuable Insights into Neurodegeneration

Antioxidants ◽  
2021 ◽  
Vol 10 (5) ◽  
pp. 694
Author(s):  
Hyungsun Park ◽  
Jongyoon Kim ◽  
Chihoon Shin ◽  
Seongju Lee
Keyword(s):  
Neurodegenerative Diseases ◽  
Redox Homeostasis ◽  
Degradation Pathway ◽  
Pharmacological Intervention ◽  
Oxygen Species ◽  
Promising Strategy ◽  
Autophagy Induction ◽  
The Relationship ◽  
The Brain ◽  
Lateral Sclerosis

Autophagy, a main degradation pathway for maintaining cellular homeostasis, and redox homeostasis have recently been considered to play protective roles in neurodegenerative diseases such as Alzheimer’s disease, Parkinson’s disease, and amyotrophic lateral sclerosis. Increased levels of reactive oxygen species (ROS) in neurons can induce mitochondrial damage and protein aggregation, thereby resulting in neurodegeneration. Oxidative stress is one of the major activation signals for the induction of autophagy. Upon activation, autophagy can remove ROS, damaged mitochondria, and aggregated proteins from the cells. Thus, autophagy can be an effective strategy to maintain redox homeostasis in the brain. However, the interaction between redox homeostasis and autophagy is not clearly elucidated. In this review, we discuss recent studies on the relationship between redox homeostasis and autophagy associated with neurodegenerative diseases and propose that autophagy induction through pharmacological intervention or genetic activation might be a promising strategy to treat these disorders.

scholarly journals Neuroprotective Effects of Magnesium L-threonate in a Hypoxic Zebrafish Model

2020 ◽  
Author(s):  
Young Sung Kim ◽  
Young Ju Won ◽  
Byung Gun Lim ◽  
Too Jae Min ◽  
Yeon-Hwa Kim ◽  
...  
Keyword(s):  
Cognitive Function ◽  
Cerebral Infarction ◽  
Cell Viability ◽  
Excitatory Amino Acid ◽  
Glutamate Transporter ◽  
Protective Effects ◽  
Triphenyltetrazolium Chloride ◽  
Zebrafish Model ◽  
Neuroprotective Effects ◽  
The Brain

Abstract Background: Hypoxia inhibits the uptake of glutamate (a major neurotransmitter in the brain closely related to cognitive function) into brain cells, and the initial response of cells to cortical hypoxia depends on glutamate. Previous studies have suggested that magnesium may have protective effects against hypoxic injuries. In particular, magnesium L-threonate (MgT) may increase magnesium ion concentrations in the brain better than MgSO4 and improve cognitive function. Methods: We evaluated cell viability under hypoxic conditions in the MgT- and MgSO4-treated human SH-SY5Y neurons, in vivo behavior using the T-maze test following hypoxia in MgT-treated zebrafish, activity of brain mitochondrial dehydrogenase by 2,3,5-triphenyltetrazolium chloride (TTC) staining, and protein expression of the excitatory amino acid transporter (EAAT) 4 glutamate transporter by western blotting.Results: Among the groups treated with hypoxia, cell viability significantly increased when pre-treated with 1 or 10 mM MgT (p=0.009 and 0.026, respectively). Despite hypoxic insult, MgT-treated zebrafish showed preferences for the red compartment (p=0.025 for distance and p=0.007 for frequency of entries), suggesting memory preservation. TTC staining showed reduced cerebral infarction and preserved absorbance in the MgT-treated zebrafish brain after hypoxia (p=0.010 compared to the hypoxia group). In addition, western blot showed upregulation of EAAT4 protein in the MgT treated group.Conclusions: Pre-treatment with MgT attenuated cell death and cerebral infarction due to hypoxia and protected cognitive function in zebrafish. In addition, MgT appeared to modulate expression of the glutamate transporter, EAAT4.

scholarly journals Neuroprotective Effects of Magnesium L-threonate in a Hypoxic Zebrafish Model

2020 ◽  
Author(s):  
Young Sung Kim ◽  
Young Ju Won ◽  
Byung Gun Lim ◽  
Too Jae Min ◽  
Yeon-Hwa Kim ◽  
...  
Keyword(s):  
Cognitive Function ◽  
Cerebral Infarction ◽  
Cell Viability ◽  
Excitatory Amino Acid ◽  
Glutamate Transporter ◽  
Protective Effects ◽  
Triphenyltetrazolium Chloride ◽  
Zebrafish Model ◽  
Neuroprotective Effects ◽  
The Brain

Abstract Background: Hypoxia inhibits the uptake of glutamate (a major neurotransmitter in the brain closely related to cognitive function) into brain cells, and the initial response of cells to cortical hypoxia depends on glutamate. Previous studies have suggested that magnesium may have protective effects against hypoxic injuries. In particular, magnesium L-threonate (MgT) may increase magnesium ion concentrations in the brain better than MgSO 4 and improve cognitive function. Methods: We evaluated cell viability under hypoxic conditions in the MgT- and MgSO 4 -treated human SH-SY5Y neurons, in vivo behavior using the T-maze test following hypoxia in MgT-treated zebrafish, activity of brain mitochondrial dehydrogenase by 2,3,5-triphenyltetrazolium chloride (TTC) staining, and protein expression of the excitatory amino acid transporter (EAAT) 4 glutamate transporter by western blotting. Results : Among the groups treated with hypoxia, cell viability significantly increased when pre-treated with 1 or 10 mM MgT (p = 0.009 and 0.026, respectively). Despite hypoxic insult, MgT-treated zebrafish showed preferences for the red compartment (p= 0.025 for distance and p= 0.007 for frequency of entries), suggesting memory preservation. TTC staining showed reduced cerebral infarction and preserved absorbance in the MgT-treated zebrafish brain after hypoxia (p=0.010 compared to the hypoxia group). In addition, western blot showed upregulation of EAAT4 protein in the MgT treated group. Conclusions: Pre-treatment with MgT attenuated cell death and cerebral infarction due to hypoxia and protected cognitive function in zebrafish. In addition, MgT appeared to modulate expression of the glutamate transporter, EAAT4.

scholarly journals Neuroprotective Effects of Magnesium L-threonate in a Hypoxic Zebrafish Model

2020 ◽  
Author(s):  
Young Sung Kim ◽  
Young Ju Won ◽  
Byung Gun Lim ◽  
Too Jae Min ◽  
Yeon-Hwa Kim ◽  
...  
Keyword(s):  
Cognitive Function ◽  
Cerebral Infarction ◽  
Cell Viability ◽  
Excitatory Amino Acid ◽  
Glutamate Transporter ◽  
Protective Effects ◽  
Triphenyltetrazolium Chloride ◽  
Zebrafish Model ◽  
Neuroprotective Effects ◽  
The Brain

Abstract Background: Hypoxia inhibits the uptake of glutamate (a major neurotransmitter in the brain closely related to cognitive function) into brain cells, and the initial response of cells to cortical hypoxia depends on glutamate. Previous studies have suggested that magnesium may have protective effects against hypoxic injuries. In particular, magnesium L-threonate (MgT) may increase magnesium ion concentrations in the brain better than MgSO 4 and improve cognitive function.Methods: We evaluated cell viability under hypoxic conditions in the MgT- and MgSO 4 -treated human SH-SY5Y neurons, in vivo behavior using the T-maze test following hypoxia in MgT-treated zebrafish, activity of brain mitochondrial dehydrogenase by 2,3,5-triphenyltetrazolium chloride (TTC) staining, and protein expression of the excitatory amino acid transporter (EAAT) 4 glutamate transporter by western blotting.Results : Among the groups treated with hypoxia, cell viability significantly increased when pre-treated with 1 or 10 mM MgT (p = 0.009 and 0.026, respectively) Despite hypoxic insult, MgT-treated zebrafish showed preferences for the red compartment (p= 0.025 for distance and p= 0.007 for frequency of entries), suggesting memory preservation. TTC staining showed reduced cerebral infarction and preserved absorbance in the MgT-treated zebrafish brain after hypoxia (p=0.010 compared to the hypoxia group). In addition, western blot showed upregulation of EAAT4 protein in the MgT treated group.Conclusions: Pre-treatment with MgT attenuated cell death and cerebral infarction due to hypoxia and protected cognitive function in zebrafish. In addition, MgT appeared to modulate expression of the glutamate transporter, EAAT4.

scholarly journals PKN1 promotes synapse maturation by inhibiting mGluR-dependent silencing through neuronal glutamate transporter activation

2020 ◽  
Vol 3 (1) ◽  
Author(s):  
Hiroki Yasuda ◽  
Hikaru Yamamoto ◽  
Kenji Hanamura ◽  
Mona Mehruba ◽  
Toshio Kawamata ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Metabotropic Glutamate Receptor ◽  
Excitatory Amino Acid ◽  
Glutamate Uptake ◽  
Critical Role ◽  
Glutamate Transporter ◽  
Wild Type ◽  
Excitatory Amino Acid Transporter ◽  
The Brain ◽  
Neuronal Glutamate Transporter

AbstractAbnormal metabotropic glutamate receptor (mGluR) activity could cause brain disorders; however, its regulation has not yet been fully understood. Here, we report that protein kinase N1 (PKN1), a protein kinase expressed predominantly in neurons in the brain, normalizes group 1 mGluR function by upregulating a neuronal glutamate transporter, excitatory amino acid transporter 3 (EAAT3), and supports silent synapse activation. Knocking out PKN1a, the dominant PKN1 subtype in the brain, unmasked abnormal input-nonspecific mGluR-dependent long-term depression (mGluR-LTD) and AMPA receptor (AMPAR) silencing in the developing hippocampus. mGluR-LTD was mimicked by inhibiting glutamate transporters in wild-type mice. Knocking out PKN1a decreased hippocampal EAAT3 expression and PKN1 inhibition reduced glutamate uptake through EAAT3. Also, synaptic transmission was immature; there were more silent synapses and fewer spines with shorter postsynaptic densities in PKN1a knockout mice than in wild-type mice. Thus, PKN1 plays a critical role in regulation of synaptic maturation by upregulating EAAT3 expression.

scholarly journals Possible expression of functional glutamate transporters in the rat testis

2004 ◽  
Vol 181 (2) ◽  
pp. 233-244 ◽  
Author(s):  
T Takarada ◽  
E Hinoi ◽  
VJ Balcar ◽  
H Taniura ◽  
Y Yoneda
Keyword(s):  
Excitatory Amino Acid ◽  
Glutamate Transporter ◽  
Immunohistochemical Analysis ◽  
Functional Expression ◽  
Excitatory Amino Acid Transporter ◽  
Peripheral Tissues ◽  
Excitatory Neurotransmitter ◽  
Rat Testis ◽  
Mitochondrial Fractions ◽  
The Brain

Neither expression nor functionality is clear in peripheral tissues with the molecular machineries required for excitatory neurotransmitter signaling by L-glutamate (Glu) in the central nervous system, while a recent study has shown that several Glu receptors are functionally expressed in the rat testis. This fact prompted us to explore the possible functional expression in the rat testis of the Glu transporters usually responsible for the regulation of extracellular Glu concentrations in the brain. RT-PCR revealed the expression, in the rat testis, of mRNA for five different subtypes of Glu transporters, in addition to that for particular subtypes of ionotropic and metabotropic Glu receptors. Glutamate transporter-1 (GLT-1) was different in the brain from that in the testis in terms of molecular sizes on Northern and Western blot analyses. In situ hybridization as well as immunohistochemical analysis showed localized expression of glutamate aspartate transporter at interstitial spaces and GLT-1 at elongated spermatids in the rat testis respectively. The expression of mRNA was localized for excitatory amino acid transporter-5 at the basal compartment of the seminiferous tubule in the rat testis. [(3)H]Glu was accumulated in testicular crude mitochondrial fractions in a temperature- and sodium-dependent saturable manner with pharmacological profiles similar to those shown in brain crude mitochondrial fractions. These results suggested that particular subtypes of central Glu transporters for the regulation of extracellular Glu concentrations in the rat testis could be constitutively and functionally expressed.

scholarly journals The BACH1/Nrf2 Axis in Brain in Down Syndrome and Transition to Alzheimer Disease-Like Neuropathology and Dementia

Antioxidants ◽  
2020 ◽  
Vol 9 (9) ◽  
pp. 779
Author(s):  
Marzia Perluigi ◽  
Antonella Tramutola ◽  
Sara Pagnotta ◽  
Eugenio Barone ◽  
D. Allan Butterfield
Keyword(s):  
Down Syndrome ◽  
Senile Plaques ◽  
Redox Homeostasis ◽  
Antioxidant Defense System ◽  
Chromosome 21 ◽  
Potential Contribution ◽  
Physiological Relevance ◽  
Increased Risk ◽  
Hyperphosphorylated Tau Protein ◽  
The Brain

Down syndrome (DS) is the most common genetic cause of intellectual disability that is associated with an increased risk to develop early-onset Alzheimer-like dementia (AD). The brain neuropathological features include alteration of redox homeostasis, mitochondrial deficits, inflammation, accumulation of both amyloid beta-peptide oligomers and senile plaques, as well as aggregated hyperphosphorylated tau protein-containing neurofibrillary tangles, among others. It is worth mentioning that some of the triplicated genes encoded are likely to cause increased oxidative stress (OS) conditions that are also associated with reduced cellular responses. Published studies from our laboratories propose that increased oxidative damage occurs early in life in DS population and contributes to age-dependent neurodegeneration. This is the result of damaged, oxidized proteins that belong to degradative systems, antioxidant defense system, neuronal trafficking. and energy metabolism. This review focuses on a key element that regulates redox homeostasis, the transcription factor Nrf2, which is negatively regulated by BACH1, encoded on chromosome 21. The role of the Nrf2/BACH1 axis in DS is under investigation, and the effects of triplicated BACH1 on the transcriptional regulation of Nrf2 are still unknown. In this review, we discuss the physiological relevance of BACH1/Nrf2 signaling in the brain and how the dysfunction of this system affects the redox homeostasis in DS neurons and how this axis may contribute to the transition of DS into DS with AD neuropathology and dementia. Further, some of the evidence collected in AD regarding the potential contribution of BACH1 to neurodegeneration in DS are also discussed.

scholarly journals Nanoparticle-Guided Brain Drug Delivery: Expanding the Therapeutic Approach to Neurodegenerative Diseases

Pharmaceutics ◽  
2021 ◽  
Vol 13 (11) ◽  
pp. 1897
Author(s):  
Claudia Riccardi ◽  
Filomena Napolitano ◽  
Daniela Montesarchio ◽  
Simone Sampaolo ◽  
Mariarosa Anna Beatrice Melone
Keyword(s):  
Neurodegenerative Diseases ◽  
Protein Misfolding ◽  
Disease Onset ◽  
Brain Targeting ◽  
Brain Drug Delivery ◽  
Alternative Approach ◽  
Genetic Mechanisms ◽  
Main Protein ◽  
Misfolding Diseases ◽  
The Brain

Neurodegenerative diseases (NDs) represent a heterogeneous group of aging-related disorders featured by progressive impairment of motor and/or cognitive functions, often accompanied by psychiatric disorders. NDs are denoted as ‘protein misfolding’ diseases or proteinopathies, and are classified according to their known genetic mechanisms and/or the main protein involved in disease onset and progression. Alzheimer’s disease (AD), Parkinson’s disease (PD) and Huntington’s disease (HD) are included under this nosographic umbrella, sharing histopathologically salient features, including deposition of insoluble proteins, activation of glial cells, loss of neuronal cells and synaptic connectivity. To date, there are no effective cures or disease-modifying therapies for these NDs. Several compounds have not shown efficacy in clinical trials, since they generally fail to cross the blood-brain barrier (BBB), a tightly packed layer of endothelial cells that greatly limits the brain internalization of endogenous substances. By engineering materials of a size usually within 1–100 nm, nanotechnology offers an alternative approach for promising and innovative therapeutic solutions in NDs. Nanoparticles can cross the BBB and release active molecules at target sites in the brain, minimizing side effects. This review focuses on the state-of-the-art of nanoengineered delivery systems for brain targeting in the treatment of AD, PD and HD.

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