KCNQ3 is the principal target of retigabine in CA1 and subicular excitatory neurons

2021 ◽  
Author(s):  
Nissi Varghese ◽  
Anna Lauritano ◽  
Maurizio Taglialatela ◽  
Anastasios Tzingounis
Keyword(s):  
Nervous System ◽  
Potassium Channel ◽  
Neuronal Excitability ◽  
Neuron Activity ◽  
Kcnq Channels ◽  
Beneficial Effects ◽  
Excitatory Neurons ◽  
The Central Nervous System ◽  
Ca1 Pyramidal Neuron ◽  
Patients With Epilepsy

Retigabine is a first-in-class potassium channel opener approved for patients with epilepsy. Unfortunately, several side effects have limited its use in clinical practice, overshadowing its beneficial effects. Multiple studies have shown that retigabine acts by enhancing the activity of members of the voltage-gated KCNQ (Kv7) potassium channel family, particularly the neuronal KCNQ channels KCNQ2-KCNQ5. However, it is currently unknown whether retigabine's action in neurons is mediated by all KCNQ neuronal channels or by only a subset. This knowledge is necessary to elucidate retigabine's mechanism of action in the central nervous system and its adverse effects and to design more effective and selective retigabine analogs. Here, we show that the action of retigabine in excitatory neurons strongly depends on the presence of KCNQ3 channels. Deletion of Kcnq3 severely limited the ability of retigabine to reduce neuronal excitability in mouse CA1 and subiculum excitatory neurons. Additionally, we report that in the absence of KCNQ3 channels, retigabine can enhance CA1 pyramidal neuron activity, leading to a greater number of action potentials and reduced spike frequency adaptation; this finding further supports a key role of KCNQ3 channels in mediating the action of retigabine. Our work provides new insight into the action of retigabine in forebrain neurons, clarifying retigabine's action in the nervous system.

The role of the tripartite synapse in the heart: how glial cells may contribute to the physiology and pathophysiology of the intracardiac nervous system

2021 ◽  
Vol 320 (1) ◽  
pp. C1-C14
Author(s):  
Angelo Tedoldi ◽  
Liam Argent ◽  
Johanna M. Montgomery
Keyword(s):  
Nervous System ◽  
Glial Cells ◽  
Neuronal Excitability ◽  
Cell Function ◽  
Active Role ◽  
High Plasma ◽  
Neuron Activity ◽  
The Central Nervous System ◽  
Intracardiac Nervous System

One of the major roles of the intracardiac nervous system (ICNS) is to act as the final site of signal integration for efferent information destined for the myocardium to enable local control of heart rate and rhythm. Multiple subtypes of neurons exist in the ICNS where they are organized into clusters termed ganglionated plexi (GP). The majority of cells in the ICNS are actually glial cells; however, despite this, ICNS glial cells have received little attention to date. In the central nervous system, where glial cell function has been widely studied, glia are no longer viewed simply as supportive cells but rather have been shown to play an active role in modulating neuronal excitability and synaptic plasticity. Pioneering studies have demonstrated that in addition to glia within the brain stem, glial cells within multiple autonomic ganglia in the peripheral nervous system, including the ICNS, can also act to modulate cardiovascular function. Clinically, patients with atrial fibrillation (AF) undergoing catheter ablation show high plasma levels of S100B, a protein produced by cardiac glial cells, correlated with decreased AF recurrence. Interestingly, S100B also alters GP neuron excitability and neurite outgrowth in the ICNS. These studies highlight the importance of understanding how glial cells can affect the heart by modulating GP neuron activity or synaptic inputs. Here, we review studies investigating glia both in the central and peripheral nervous systems to discuss the potential role of glia in controlling cardiac function in health and disease, paying particular attention to the glial cells of the ICNS.

Understanding Neuropathic Pain

CNS Spectrums ◽  
2005 ◽  
Vol 10 (4) ◽  
pp. 298-308 ◽  
Author(s):  
Walter Zieglgänsberger ◽  
Achim Berthele ◽  
Thomas R. Tölle
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Neuropathic Pain ◽  
Neuronal Excitability ◽  
Traumatic Injury ◽  
Nerve Fibers ◽  
Cellular Events ◽  
Excitatory Neurotransmitters ◽  
The Central Nervous System ◽  
Activity Dependent

AbstractNeuropathic pain is defined as a chronic pain condition that occurs or persists after a primary lesion or dysfunction of the peripheral or central nervous system. Traumatic injury of peripheral nerves also increases the excitability of nociceptors in and around nerve trunks and involves components released from nerve terminals (neurogenic inflammation) and immunological and vascular components from cells resident within or recruited into the affected area. Action potentials generated in nociceptors and injured nerve fibers release excitatory neurotransmitters at their synaptic terminals such as L-glutamate and substance P and trigger cellular events in the central nervous system that extend over different time frames. Short-term alterations of neuronal excitability, reflected for example in rapid changes of neuronal discharge activity, are sensitive to conventional analgesics, and do not commonly involve alterations in activity-dependent gene expression. Novel compounds and new regimens for drug treatment to influence activity-dependent long-term changes in pain transducing and suppressive systems (pain matrix) are emerging.

scholarly journals Growth-Promoting Treatment Screening for Corticospinal Neurons in Mouse and Man

2020 ◽  
Vol 40 (8) ◽  
pp. 1327-1338
Author(s):  
Nicholas Hanuscheck ◽  
Andrea Schnatz ◽  
Carine Thalman ◽  
Steffen Lerch ◽  
Yvonne Gärtner ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Nervous System ◽  
Interleukin 4 ◽  
Regenerative Capacity ◽  
Beneficial Effects ◽  
Cord Injury ◽  
Tissue Culture Model ◽  
The Central Nervous System ◽  
Cone Formation ◽  
New Treatments

Abstract Neurons of the central nervous system (CNS) that project long axons into the spinal cord have a poor axon regenerative capacity compared to neurons of the peripheral nervous system. The corticospinal tract (CST) is particularly notorious for its poor regeneration. Because of this, traumatic spinal cord injury (SCI) is a devastating condition that remains as yet uncured. Based on our recent observations that direct neuronal interleukin-4 (IL-4) signaling leads to repair of axonal swellings and beneficial effects in neuroinflammation, we hypothesized that IL-4 acts directly on the CST. Here, we developed a tissue culture model for CST regeneration and found that IL-4 promoted new growth cone formation after axon transection. Most importantly, IL-4 directly increased the regenerative capacity of both murine and human CST axons, which corroborates its regenerative effects in CNS damage. Overall, these findings serve as proof-of-concept that our CST regeneration model is suitable for fast screening of new treatments for SCI.

Immunohistochemical localization of the voltage-gated potassium channel subunit Kv1.4 in the central nervous system of the adult rat

2003 ◽  
Vol 26 (3) ◽  
pp. 209-224 ◽  
Author(s):  
Rafael Luján ◽  
Carlos de Cabo de la Vega ◽  
Eduardo Dominguez del Toro ◽  
Juan J Ballesta ◽  
Manuel Criado ◽  
...  
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Potassium Channel ◽  
Immunohistochemical Localization ◽  
Voltage Gated ◽  
Adult Rat ◽  
The Central Nervous System

scholarly journals Neuroprotective Aspects of Cannabinoid Compounds

2020 ◽  
Vol 5 (2) ◽  
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Molecular Mechanisms ◽  
Reliable Data ◽  
Protective Effects ◽  
Neuroprotective Agents ◽  
Beneficial Effects ◽  
Cannabinoid Compounds ◽  
The Central Nervous System ◽  
Effective Use

The accumulation of reliable data on the effects of cannabinoids is essential for understanding their possible beneficial effects on the central nervous system (CNS). Investigating individual substances along with the action of different combinations may show new possibilities for cannabinoids as neuroprotective agents. The data collected so far reveals the complexity of the mechanism of cannabinoids action on CNS, and even more complex and poorly understood are the effects when combined. Moreover, combining cannabinoids with different drugs and chemicals may lead to a decrease in beneficial effects. These characteristics of their action emphasize the complexity of the molecular mechanisms of neuroprotection and the lack of reliable information that may contribute to the safe and effective use of cannabinoids as medicines with valuable neuroprotective properties. The current brief review summarizes present data related to the protective effects of some cannabinoids on CNS and possible mechanisms involved in cannabinoid-mediated neuroprotection.

scholarly journals A Hypothesis Regarding how Sleep can Calibrate Neuronal Excitability in the Central Nervous System and thereby Offer Stability, Sensitivity and the Best Possible Cognitive Function

2019 ◽  
Author(s):  
Sture Hansson
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Neuronal Excitability ◽  
Slow Wave Sleep ◽  
Reaction Times ◽  
Epileptic Seizures ◽  
Neuronal Firing ◽  
Sensory Stimuli ◽  
The Central Nervous System ◽  
Function Of Sleep

The function of sleep in mammal and other vertebrates is one of the great mysteries of biology. Many hypotheses have been proposed, but few of these have made even the slightest attempt to explain the essence of sleep - the uncompromising need for reversible unconsciousness. During sleep, epiphenomena - often of a somatic character - occur, but these cannot explain the core function of sleep. One answer could be hidden in the observations made for long periods of time of the function of the central nervous system (CNS). The CNS is faced with conflicting requirements on stability and excitability. A high level of excitability is desirable, and is also a prerequisite for sensitivity and quick reaction times; however, it can also lead to instability and the risk of feedback, with life-threatening epileptic seizures. Activity-dependent negative feedback in neuronal excitability improves stability in the short term, but not to the degree that is required. A hypothesis is presented here demonstrating how calibration of individual neurons - an activity which occurs only during sleep - can establish the balanced and highest possible excitability while also preserving stability in the CNS. One example of a possible mechanism is the observation of slow oscillations in EEGs made on birds and mammals during slow wave sleep. Calibration to a genetically determined level of excitability could take place in individual neurons during the slow oscillation, so that action potentials are generated during the oscillations “up-phase”. This can only take place offline, which explains the need for sleep. The hypothesis can explain phenomena such as the need for unconsciousness during sleep, with the disconnection of sensory stimuli, slow EEG oscillations, the relationship of sleep and epilepsy, age, the effects of sleep on neuronal firing rate and the effects of sleep deprivation and sleep homeostasis. This is with regard primarily to mammals, including humans, but also all other vertebrates.

Central mineralocorticoid receptor blockade improves volume regulation and reduces sympathetic drive in heart failure

2001 ◽  
Vol 281 (5) ◽  
pp. H2241-H2251 ◽  
Author(s):  
Joseph Francis ◽  
Robert M. Weiss ◽  
Shun-Guang Wei ◽  
Alan Kim Johnson ◽  
Terry G. Beltz ◽  
...  
Keyword(s):  
Heart Failure ◽  
Central Nervous System ◽  
Nervous System ◽  
Volume Regulation ◽  
Critical Role ◽  
Coronary Artery Ligation ◽  
Artery Ligation ◽  
Water Excretion ◽  
Beneficial Effects ◽  
The Central Nervous System

The mineralocorticoid (MC) receptor antagonist spironolactone (SL) improves morbidity and mortality in patients with congestive heart failure (CHF). We tested the hypothesis that the central nervous system actions of SL contribute to its beneficial effects. SL (100 ng/h for 28 days) or ethanol vehicle (VEH) was administered intracerebroventricularly or intraperitoneally to rats with CHF induced by coronary artery ligation (CL) and to SHAM-operated controls. The intracerebroventricular SL treatment prevented the increase in sodium appetite and the decreases in sodium and water excretion observed within a week of CL in VEH-treated CHF rats. Intraperitoneal SL also improved volume regulation in the CHF rats, but only after 3 wk of treatment. Four weeks of SL treatment, either intracerebroventricularly or intraperitoneally, ameliorated both the increase in sympathetic drive and the impaired baroreflex function observed in VEH-treated CHF rats. These findings suggest that activation of MC receptors in the central nervous system plays a critical role in the altered volume regulation and augmented sympathetic drive that characterize clinical heart failure.

The Facilitation and Evocation of Seizures

1993 ◽  
Vol 162 (6) ◽  
pp. 759-764 ◽  
Author(s):  
D. Antebi ◽  
J. Bird
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Seizure Frequency ◽  
Psychological Changes ◽  
Epileptic Patients ◽  
Independent States ◽  
The Central Nervous System ◽  
Patients With Epilepsy

The finding that seizures can be precipitated in some epileptic patients by stimuli which originate from outside the central nervous system is not new. The influence of psychological changes on seizure frequency has, however, been much more difficult to determine. Patients who become aware of such associations may gain some control over their seizures. One hundred randomly selected out-patients with epilepsy were asked about their awareness of such associations and whether, as a consequence, they believed they had any control of their seizures. Ninety-two reported associations between seizures and facilitators or precipitants. The group who had made associations between independent states or stimuli and their seizures were more likely to have poorly controlled seizures and to be taking more anticonvulsants. Many had used this knowledge to control their seizures.

scholarly journals A Novel Prodrug Approach for Central Nervous System-Selective Estrogen Therapy

Molecules ◽  
2019 ◽  
Vol 24 (22) ◽  
pp. 4197 ◽  
Author(s):  
Katalin Prokai-Tatrai ◽  
Laszlo Prokai
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Estrogen Therapy ◽  
High Concentration ◽  
Beneficial Effects ◽  
Non Invasive ◽  
Site Of Action ◽  
The Central Nervous System ◽  
And Gender ◽  
Preclinical Animal Models

Beneficial effects of estrogens in the central nervous system (CNS) results from the synergistic combination of their well-orchestrated genomic and non-genomic actions, making them potential broad-spectrum neurotherapeutic agents. However, owing to unwanted peripheral hormonal burdens by any currently known non-invasive drug administrations, the development of estrogens as safe pharmacotherapeutic modalities cannot be realized until they are confined specifically and selectively to the site of action. We have developed small-molecule bioprecursor prodrugs carrying the para-quinol scaffold on the steroidal A-ring that are preferentially metabolized in the CNS to the corresponding estrogens. Here, we give an overview of our discovery of these prodrugs. Selected examples are shown to illustrate that, independently of the route of administrations and duration of treatments, these agents produce high concentration of estrogens only in the CNS without peripheral hormonal liability. 10β,17β-Dihydroxyestra-1,4-dien-3-one (DHED) has been the best-studied representative of this novel type of prodrugs for brain and retina health. Specific applications in preclinical animal models of centrally-regulated and estrogen-responsive human diseases, including neurodegeneration, menopausal symptoms, cognitive decline and depression, are discussed to demonstrate the translational potential of our prodrug approach for CNS-selective and gender-independent estrogen therapy with inherent therapeutic safety.

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