scholarly journals Oxidative Stress Induces Disruption of the Axon Initial Segment

ASN NEURO ◽  
2017 ◽  
Vol 9 (6) ◽  
pp. 175909141774542 ◽  
Author(s):  
Kareem C. Clark ◽  
Brooke A. Sword ◽  
Jeffrey L. Dupree
Keyword(s):  
Oxidative Stress ◽  
Central Nervous System ◽  
Nervous System ◽  
Cortical Neurons ◽  
Initial Segment ◽  
Reactive Oxygen ◽  
Axon Initial Segment ◽  
Voltage Dependent ◽  
Reversible Loss

The axon initial segment (AIS), the domain responsible for action potential initiation and maintenance of neuronal polarity, is targeted for disruption in a variety of central nervous system pathological insults. Previous work in our laboratory implicates oxidative stress as a potential mediator of structural AIS alterations in two separate mouse models of central nervous system inflammation, as these effects were attenuated following reactive oxygen species scavenging and NADPH oxidase-2 ablation. While these studies suggest a role for oxidative stress in modulation of the AIS, the direct effects of reactive oxygen and nitrogen species (ROS/RNS) on the stability of this domain remain unclear. Here, we demonstrate that oxidative stress, as induced through treatment with 3-morpholinosydnonimine (SIN-1), a spontaneous ROS/RNS generator, drives a reversible loss of AIS protein clustering in primary cortical neurons in vitro. Pharmacological inhibition of both voltage-dependent and intracellular calcium (Ca2+) channels suggests that this mechanism of AIS disruption involves Ca2+ entry specifically through L-type voltage-dependent Ca2+ channels and its release from IP3-gated intracellular stores. Furthermore, ROS/RNS-induced AIS disruption is dependent upon activation of calpain, a Ca2+-activated protease previously shown to drive AIS modulation. Overall, we demonstrate for the first time that oxidative stress, as induced through exogenously applied ROS/RNS, is capable of driving structural alterations in the AIS complex.

scholarly journals An axon initial segment is required for temporal precision in action potential encoding by neuronal populations

2018 ◽  
Vol 4 (11) ◽  
pp. eaau8621 ◽  
Author(s):  
Elinor Lazarov ◽  
Melanie Dannemeyer ◽  
Barbara Feulner ◽  
Jörg Enderlein ◽  
Michael J. Gutnick ◽  
...  
Keyword(s):  
Initial Segment ◽  
Axon Initial Segment ◽  
High Concentration ◽  
Information Encoding ◽  
Temporal Precision ◽  
Network Function ◽  
Evolutionary Innovation ◽  
Voltage Dependent ◽  
Vitro Model

Central neurons initiate action potentials (APs) in the axon initial segment (AIS), a compartment characterized by a high concentration of voltage-dependent ion channels and specialized cytoskeletal anchoring proteins arranged in a regular nanoscale pattern. Although the AIS was a key evolutionary innovation in neurons, the functional benefits it confers are not clear. Using a mutation of the AIS cytoskeletal protein βIV-spectrin, we here establish an in vitro model of neurons with a perturbed AIS architecture that retains nanoscale order but loses the ability to maintain a high NaV density. Combining experiments and simulations, we show that a high NaV density in the AIS is not required for axonal AP initiation; it is, however, crucial for a high bandwidth of information encoding and AP timing precision. Our results provide the first experimental demonstration of axonal AP initiation without high axonal channel density and suggest that increasing the bandwidth of the neuronal code and, hence, the computational efficiency of network function, was a major benefit of the evolution of the AIS.

scholarly journals Regional Differences in Viral Growth and Central Nervous System Injury Correlate with Apoptosis

2004 ◽  
Vol 78 (10) ◽  
pp. 5466-5475 ◽  
Author(s):  
Sarah M. Richardson-Burns ◽  
Kenneth L. Tyler
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Cortical Neurons ◽  
Fatty Acid Synthase ◽  
Central Nervous System Injury ◽  
Antigenic Variant ◽  
Viral Yield ◽  
Induced Apoptosis ◽  
Restricted Pattern

ABSTRACT Infection of neonatal mice with reovirus T3 Dearing (T3D), the prototypic neurotropic reovirus, causes fatal encephalitis associated with neuronal injury and virus-induced apoptosis throughout the brain. T3D variant K (VarK) is an antigenic variant that has a nearly 1 million-fold reduction in neurovirulence following intracerebral (i.c.) inoculation compared to T3D and a restricted pattern of central nervous system injury with damage limited to the hippocampus, sparing other brain regions. We wished to determine whether the restricted pattern of VarK-induced injury was due to a reduced capacity to replicate in or injure cortical, as opposed to hippocampal, tissue. We found that following i.c. inoculation, VarK grew to similar titers as T3D in the hippocampus but had significantly lower titers in the cortex. Both viruses grew to identical titers and infected the same percentage of cells in mouse primary hippocampal cultures (MHC). In mouse primary cortical cultures (MCC) both the number of infected cells and the viral yield per infected cell were significantly lower for VarK than T3D. VarK-induced apoptosis was limited to the hippocampus in vivo, and in vitro both viruses induced apoptosis equally in MHC but VarK induced significantly less apoptosis than T3D in MCC. Growth of T3D in MCC was reduced to levels comparable to those of VarK following treatment of MCC with caspase inhibitors. Conversely, induction of apoptosis in VarK-infected MCC with fatty acid synthase-activating antibody significantly enhanced viral yield. These results suggest that the decreased neurovirulence of VarK may be due to its failure to efficiently induce apoptosis in cortical neurons.

scholarly journals Protrudin functions as a scaffold in the endoplasmic reticulum to support axon regeneration in the adult central nervous system

2020 ◽  
Author(s):  
Veselina Petrova ◽  
Craig S. Pearson ◽  
James R. Tribble ◽  
Andrea G. Solano ◽  
Evan Reid ◽  
...  
Keyword(s):  
Central Nervous System ◽  
Endoplasmic Reticulum ◽  
Nervous System ◽  
Cortical Neurons ◽  
Binding Properties ◽  
Adult Central Nervous System ◽  
Low Levels ◽  
Cellular Components

SummaryAdult mammalian central nervous system axons have intrinsically poor regenerative capacity, so axonal injury has permanent consequences. One approach to enhancing regeneration is to increase the axonal supply of growth molecules and organelles. We achieved this by expressing the adaptor molecule Protrudin which is normally found at low levels in non-regenerative neurons. Elevated Protrudin expression enabled robust central nervous system regeneration both in vitro in primary cortical neurons and in vivo in the injured adult optic nerve. Protrudin overexpression facilitated the accumulation of endoplasmic reticulum, integrins and Rab11 endosomes in the distal axon, whilst removing Protrudin’s endoplasmic reticulum localization, kinesin-binding or phosphoinositide-binding properties abrogated the regenerative effects. These results demonstrate that Protrudin promotes regeneration by functioning as a scaffold to link axonal organelles, motors and membranes, establishing important roles for these cellular components in mediating regeneration in the adult central nervous system.

scholarly journals Protrudin functions from the endoplasmic reticulum to support axon regeneration in the adult CNS

2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Veselina Petrova ◽  
Craig S. Pearson ◽  
Jared Ching ◽  
James R. Tribble ◽  
Andrea G. Solano ◽  
...  
Keyword(s):  
Central Nervous System ◽  
Endoplasmic Reticulum ◽  
Nervous System ◽  
Cortical Neurons ◽  
Binding Properties ◽  
Adaptor Molecule ◽  
Low Levels ◽  
Cellular Components

Abstract Adult mammalian central nervous system axons have intrinsically poor regenerative capacity, so axonal injury has permanent consequences. One approach to enhancing regeneration is to increase the axonal supply of growth molecules and organelles. We achieved this by expressing the adaptor molecule Protrudin which is normally found at low levels in non-regenerative neurons. Elevated Protrudin expression enabled robust central nervous system regeneration both in vitro in primary cortical neurons and in vivo in the injured adult optic nerve. Protrudin overexpression facilitated the accumulation of endoplasmic reticulum, integrins and Rab11 endosomes in the distal axon, whilst removing Protrudin’s endoplasmic reticulum localization, kinesin-binding or phosphoinositide-binding properties abrogated the regenerative effects. These results demonstrate that Protrudin promotes regeneration by functioning as a scaffold to link axonal organelles, motors and membranes, establishing important roles for these cellular components in mediating regeneration in the adult central nervous system.

Brain benzodiazepine levels following intravenous administration of [3H]diazepam: Relationship to the potentiation of purinergic depression of central nervous system neurons

1979 ◽  
Vol 57 (9) ◽  
pp. 1040-1042 ◽  
Author(s):  
Phil Skolnick ◽  
Steven M. Paul ◽  
Paul J. Marangos
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Cerebral Cortex ◽  
Intravenous Injection ◽  
Cortical Neurons ◽  
Benzodiazepine Receptors ◽  
Time Schedule ◽  
Adenosine Uptake ◽  
Cerebral Cortical Neurons

Levels of [3H] benzodiazepine were measured in rat cerebral cortex following intravenous injection of [3H]diazepam using a dose and time schedule reported to elicit a marked potentiation of the depressant effects of iontophoretically applied 5′-AMP to rat cerebral cortical neurons. The levels of [3H]benzodiazepine obtained strongly suggest (i) that blockade of adenosine uptake as a mechanism for this potentiation is not consistent with the potency of diazepam as an inhibitor of adenosine uptake in vitro, and (ii) that a potentiative interaction of adenosine and diazepam may reflect the binding of these compounds to benzodiazepine receptors.

scholarly journals Cyp1b1-deficient retinal astrocytes are more proliferative and migratory and are protected from oxidative stress and inflammation

2019 ◽  
Vol 316 (6) ◽  
pp. C767-C781 ◽  
Author(s):  
Juliana Falero-Perez ◽  
Christine M. Sorenson ◽  
Nader Sheibani
Keyword(s):  
Oxidative Stress ◽  
Central Nervous System ◽  
Nervous System ◽  
Connexin 43 ◽  
Mapk Signaling ◽  
Vascular Cells ◽  
Adhesive Properties ◽  
The Central Nervous System ◽  
The Impact

Astrocytes (ACs) are the most abundant cells in the central nervous system. Retinal ACs play an important role in maintaining the integrity of retinal neurovascular function, and their dysfunction contributes to the pathogenesis of various eye diseases including diabetic retinopathy. Cytochrome P450 1B1 (CYP1B1) expression in the neurovascular structures of the central nervous system including ACs has been reported. We previously showed that CYP1B1 expression is a key regulator of redox homeostasis in retinal vascular cells. Its deficiency in mice resulted in increased oxidative stress and attenuation of angiogenesis in vivo and proangiogenic activity of retinal vascular cells in vitro. Here, using retinal ACs prepared from wild-type ( Cyp1b1+/+) and Cyp1b1-deficient ( Cyp1b1−/−) mice, we determined the impact of Cyp1b1 expression on retinal AC function. We showed that Cyp1b1−/− retinal ACs were more proliferative and migratory. These cells also produced increased amounts of fibronectin and its receptors, αvβ3- and α5β1-integrin. These results were consistent with the increased adhesive properties of Cyp1b1−/− ACs and their lack of ability to form a network in Matrigel. This was reversed by reexpression of Cyp1b1 in Cyp1b1−/− ACs. Although no significant changes were observed in Akt/SRC/MAPK signaling pathways, production of inflammatory mediators bone morphogenetic protein-7 (BMP-7) and monocyte chemoattractant protein-1 (MCP-1) was decreased in Cyp1b1−/− ACs. Cyp1b1−/− ACs also showed increased levels of connexin 43 phosphorylation and cluster of differentiation 38 expression when challenged with H2O2. These results are consistent with increased proliferation and diminished oxidative stress in Cyp1b1−/− cells. Thus, Cyp1b1 expression in ACs plays an important role in retinal neurovascular homeostasis.

Neural Stem Cells to Glial Cells an Important Factor for Brain Injury

2020 ◽  
Author(s):  
Prithiv K R Kumar
Keyword(s):  
Stem Cells ◽  
Central Nervous System ◽  
Nervous System ◽  
Neural Stem Cells ◽  
Glial Cells ◽  
Brain Injuries ◽  
The Body ◽  
The Central Nervous System ◽  
Near Future

Stem cells have the capacity to differentiate into any type of cell or organ. Stems cell originate from any part of the body, including the brain. Brain cells or rather neural stem cells have the capacitive advantage of differentiating into the central nervous system leading to the formation of neurons and glial cells. Neural stem cells should have a source by editing DNA, or by mixings chemical enzymes of iPSCs. By this method, a limitless number of neuron stem cells can be obtained. Increase in supply of NSCs help in repairing glial cells which in-turn heal the central nervous system. Generally, brain injuries cause motor and sensory deficits leading to stroke. With all trials from novel therapeutic methods to enhanced rehabilitation time, the economy and quality of life is suppressed. Only PSCs have proven effective for grafting cells into NSCs. Neurons derived from stem cells is the only challenge that limits in-vitro usage in the near future.

scholarly journals Beyond Oncological Hyperthermia: Physically Drivable Magnetic Nanobubbles as Novel Multipurpose Theranostic Carriers in the Central Nervous System

Molecules ◽  
2020 ◽  
Vol 25 (9) ◽  
pp. 2104 ◽  
Author(s):  
Eleonora Ficiarà ◽  
Shoeb Anwar Ansari ◽  
Monica Argenziano ◽  
Luigi Cangemi ◽  
Chiara Monge ◽  
...  
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Brain Tumors ◽  
Ad Hoc ◽  
Superparamagnetic Iron Oxide ◽  
Conventional Radiotherapy ◽  
The Central Nervous System ◽  
Magnetic Resonance Imaging Mri ◽  
The Brain

Magnetic Oxygen-Loaded Nanobubbles (MOLNBs), manufactured by adding Superparamagnetic Iron Oxide Nanoparticles (SPIONs) on the surface of polymeric nanobubbles, are investigated as theranostic carriers for delivering oxygen and chemotherapy to brain tumors. Physicochemical and cyto-toxicological properties and in vitro internalization by human brain microvascular endothelial cells as well as the motion of MOLNBs in a static magnetic field were investigated. MOLNBs are safe oxygen-loaded vectors able to overcome the brain membranes and drivable through the Central Nervous System (CNS) to deliver their cargoes to specific sites of interest. In addition, MOLNBs are monitorable either via Magnetic Resonance Imaging (MRI) or Ultrasound (US) sonography. MOLNBs can find application in targeting brain tumors since they can enhance conventional radiotherapy and deliver chemotherapy being driven by ad hoc tailored magnetic fields under MRI and/or US monitoring.

Brain organoids: a promising model to assess oxidative stress‐induced Central Nervous System damage

2021 ◽  
Author(s):  
Foluwasomi A. Oyefeso ◽  
Alysson R. Muotri ◽  
Christopher G. Wilson ◽  
Michael J. Pecaut
Keyword(s):  
Oxidative Stress ◽  
Central Nervous System ◽  
Nervous System ◽  
Central Nervous System Damage
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