scholarly journals The Good, the Bad, and the Deadly: Adenosinergic Mechanisms Underlying Sudden Unexpected Death in Epilepsy

2021 ◽  
Vol 15 ◽  
Author(s):  
Benton Purnell ◽  
Madhuvika Murugan ◽  
Raja Jani ◽  
Detlev Boison
Keyword(s):  
Neuronal Activity ◽  
Neuronal Excitability ◽  
Receptor Activation ◽  
Sudden Unexpected Death ◽  
Unexpected Death ◽  
Neuroprotective Effects ◽  
Respiratory Dysfunction ◽  
Extracellular Adenosine ◽  
Hypoxic Conditions ◽  
Adenosine Signaling

Adenosine is an inhibitory modulator of neuronal excitability. Neuronal activity results in increased adenosine release, thereby constraining excessive excitation. The exceptionally high neuronal activity of a seizure results in a surge in extracellular adenosine to concentrations many-fold higher than would be observed under normal conditions. In this review, we discuss the multifarious effects of adenosine signaling in the context of epilepsy, with emphasis on sudden unexpected death in epilepsy (SUDEP). We describe and categorize the beneficial, detrimental, and potentially deadly aspects of adenosine signaling. The good or beneficial characteristics of adenosine signaling in the context of seizures include: (1) its direct effect on seizure termination and the prevention of status epilepticus; (2) the vasodilatory effect of adenosine, potentially counteracting postictal vasoconstriction; (3) its neuroprotective effects under hypoxic conditions; and (4) its disease modifying antiepileptogenic effect. The bad or detrimental effects of adenosine signaling include: (1) its capacity to suppress breathing and contribute to peri-ictal respiratory dysfunction; (2) its contribution to postictal generalized EEG suppression (PGES); (3) the prolonged increase in extracellular adenosine following spreading depolarization waves may contribute to postictal neuronal dysfunction; (4) the excitatory effects of A2A receptor activation is thought to exacerbate seizures in some instances; and (5) its potential contributions to sleep alterations in epilepsy. Finally, the adverse effects of adenosine signaling may potentiate a deadly outcome in the form of SUDEP by suppressing breathing and arousal in the postictal period. Evidence from animal models suggests that excessive postictal adenosine signaling contributes to the pathophysiology of SUDEP. The goal of this review is to discuss the beneficial, harmful, and potentially deadly roles that adenosine plays in the context of epilepsy and to identify crucial gaps in knowledge where further investigation is necessary. By better understanding adenosine dynamics, we may gain insights into the treatment of epilepsy and the prevention of SUDEP.

scholarly journals Altered A-type potassium channel function in the nucleus tractus solitarii in acquired temporal lobe epilepsy

2019 ◽  
Vol 121 (1) ◽  
pp. 177-187 ◽  
Author(s):  
Isabel D. Derera ◽  
Katalin Cs. Smith ◽  
Bret N. Smith
Keyword(s):  
Temporal Lobe Epilepsy ◽  
Mouse Models ◽  
Temporal Lobe ◽  
Neuronal Excitability ◽  
Gabaergic Neurons ◽  
Nucleus Tractus Solitarii ◽  
Sudden Unexpected Death ◽  
Inactivation Kinetics ◽  
Unexpected Death ◽  
Increased Risk

Sudden unexpected death in epilepsy (SUDEP) is among the leading causes of death in people with epilepsy. Individuals with temporal lobe epilepsy (TLE) have a high risk for SUDEP because the seizures are often medically intractable. Neurons in the nucleus tractus solitarii (NTS) have been implicated in mouse models of SUDEP and play a critical role in modulating cardiorespiratory and autonomic output. Increased neuronal excitability of inhibitory, GABAergic neurons in the NTS develops during epileptogenesis, and NTS dysfunction has been implicated in mouse models of SUDEP. In this study we used the pilocarpine-induced status epilepticus model of TLE (i.e., pilo-SE mice) to investigate the A-type voltage-gated K+ channel as a potential contributor to increased excitability in GABAergic NTS neurons during epileptogenesis. Compared with age-matched control mice, pilo-SE mice displayed an increase in spontaneous action potential frequency and half-width 9–12 wk after treatment. Activity of GABAergic NTS neurons from pilo-SE mice showed less sensitivity to 4-aminopyridine. Correspondingly, reduced A-type K+ current amplitude was detected in these neurons, with no change in activation or inactivation kinetics. No changes were observed in Kv4.1, Kv4.2, Kv4.3, KChIP1, KChIP3, or KChIP4 mRNA expression. These changes contribute to the increased excitability in GABAergic NTS neurons that develops in TLE and may provide insight into potential mechanisms contributing to the increased risk for cardiorespiratory collapse and SUDEP in this model. NEW & NOTEWORTHY Sudden unexpected death in epilepsy (SUDEP) is a leading cause of death in epilepsy, and dysfunction in central autonomic neurons may play a role. In a mouse model of acquired epilepsy, GABAergic neurons in the nucleus tractus solitarii developed a reduced amplitude of the A-type current, which contributes to the increased excitability seen in these neurons during epileptogenesis. Neuronal excitability changes in inhibitory central vagal circuitry may increase the risk for cardiorespiratory collapse and SUDEP.

Severe pulmonary congestion in a near miss at the first seizure: Further evidence for respiratory dysfunction in sudden unexpected death in epilepsy

2009 ◽  
Vol 14 (4) ◽  
pp. 701-702 ◽  
Author(s):  
Marianna Pezzella ◽  
Pasquale Striano ◽  
Clotilde Ciampa ◽  
Luca Errichiello ◽  
Pietro Penza ◽  
...  
Keyword(s):  
Near Miss ◽  
Sudden Unexpected Death ◽  
Pulmonary Congestion ◽  
Unexpected Death ◽  
Respiratory Dysfunction

scholarly journals Respiratory dysfunction progresses with age inKcna1-null mice, a model of sudden unexpected death in epilepsy

Epilepsia ◽  
2018 ◽  
Vol 59 (2) ◽  
pp. 345-357 ◽  
Author(s):  
Kristina A. Simeone ◽  
Jodi Hallgren ◽  
Charles S. Bockman ◽  
Ankita Aggarwal ◽  
Vikash Kansal ◽  
...  
Keyword(s):  
Sudden Unexpected Death ◽  
Unexpected Death ◽  
Respiratory Dysfunction

scholarly journals Beneficial and detrimental role of adenosine signaling in diseases and therapy

2015 ◽  
Vol 119 (10) ◽  
pp. 1173-1182 ◽  
Author(s):  
Hong Liu ◽  
Yang Xia
Keyword(s):  
Disease Progression ◽  
Tissue Injury ◽  
Acute Stage ◽  
Therapeutic Effects ◽  
Extracellular Adenosine ◽  
Hypoxic Conditions ◽  
Substantial Progress ◽  
Disease Stages ◽  
Adenosine Signaling

Adenosine is a major signaling nucleoside that orchestrates cellular and tissue adaptation under energy depletion and ischemic/hypoxic conditions by activation of four G protein-coupled receptors (GPCR). The regulation and generation of extracellular adenosine in response to stress are critical in tissue protection. Both mouse and human studies reported that extracellular adenosine signaling plays a beneficial role during acute states. However, prolonged excess extracellular adenosine is detrimental and contributes to the development and progression of various chronic diseases. In recent years, substantial progress has been made to understand the role of adenosine signaling in different conditions and to clarify its significance during the course of disease progression in various organs. These efforts have and will identify potential therapeutic possibilities for protection of tissue injury at acute stage by upregulation of adenosine signaling or attenuation of chronic disease progression by downregulation of adenosine signaling. This review is to summarize current progress and the importance of adenosine signaling in different disease stages and its potential therapeutic effects.

ECG-Patterns of Focal Epileptic Seizures, the Role in Sudden Unexpected Death in Epilepsy: A Prospective Long-Term Study

2019 ◽  
Author(s):  
Svetlana Serdyuk ◽  
Karapet V. Davtyan ◽  
Sergey G. Burd ◽  
Oksana M. Drapkina ◽  
Sergey A. Boytsov ◽  
...  
Keyword(s):  
Epileptic Seizures ◽  
Sudden Unexpected Death ◽  
Unexpected Death ◽  
Term Study ◽  
Long Term Study

scholarly journals Contribution of Ionotropic Glutamatergic Receptors to Excitability and Attentional Signals in Macaque Frontal Eye Field

2021 ◽  
Author(s):  
Miguel Dasilva ◽  
Christian Brandt ◽  
Marc Alwin Gieselmann ◽  
Claudia Distler ◽  
Alexander Thiele
Keyword(s):  
Attentional Control ◽  
Large Scale ◽  
Neuronal Excitability ◽  
Cell Types ◽  
Receptor Activation ◽  
Frontal Eye Field ◽  
Control Signals ◽  
Cognitive Operations ◽  
Eye Field ◽  
Large Scale Networks

Abstract Top-down attention, controlled by frontal cortical areas, is a key component of cognitive operations. How different neurotransmitters and neuromodulators flexibly change the cellular and network interactions with attention demands remains poorly understood. While acetylcholine and dopamine are critically involved, glutamatergic receptors have been proposed to play important roles. To understand their contribution to attentional signals, we investigated how ionotropic glutamatergic receptors in the frontal eye field (FEF) of male macaques contribute to neuronal excitability and attentional control signals in different cell types. Broad-spiking and narrow-spiking cells both required N-methyl-D-aspartic acid and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor activation for normal excitability, thereby affecting ongoing or stimulus-driven activity. However, attentional control signals were not dependent on either glutamatergic receptor type in broad- or narrow-spiking cells. A further subdivision of cell types into different functional types using cluster-analysis based on spike waveforms and spiking characteristics did not change the conclusions. This can be explained by a model where local blockade of specific ionotropic receptors is compensated by cell embedding in large-scale networks. It sets the glutamatergic system apart from the cholinergic system in FEF and demonstrates that a reduction in excitability is not sufficient to induce a reduction in attentional control signals.

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