Enhanced Tonic GABAA Inhibition in Typical Absence Epilepsy . function of GABA transporters has also been reported in nonabsence seizure models (9,10), . The impact of the methylxanthines caffeine and theophylline on seizures and .. 10 to times higher concentrations are needed to inhibit GABAARs or PDE. Application of 10μM rosiglitazone significantly suppressed In Vitro Seizures in Hippocampal Slice by Inhibiting Presynaptic Glutamate.
Seizures 10. It Inhibits
Conversely, A 1 R agonists are highly effective in the suppression of seizures Benarroch ; Fredholm ; Jacobson and Gao , and have been demonstrated to suppress seizures that are resistant to conventional antiepileptic drugs Gouder et al.
Decreased extracellular adenosine levels and reduced A 1 R activation as a consequence of kindling or caused by hypercapnia in a hippocampal slice preparation provide a plausible mechanisms for seizure generation Dulla et al. In adult brain synaptic levels of adenosine are largely regulated by an astrocyte-based adenosine cycle Boison Under physiological conditions synaptic adenosine is largely derived from vesicular release of ATP from astrocytes followed by extracellular cleavage into adenosine Pascual et al.
In contrast to conventional neurotransmitters, such as glutamate or glycine, there is no transporter-based regulatory mechanism to terminate the synaptic activity of adenosine. Due to the presence of two types of equilibrative nucleoside transporters in the astrocyte membrane Baldwin et al. ADK has recently been identified as a molecular link between astrogliosis and neuronal hyperexcitability in epilepsy Li et al.
Astrogliosis — a pathological hallmark of the epileptic brain — is associated with upregulation of the adenosine removing enzyme ADK Gouder et al.
Remarkably, the development of spontaneous electrographic seizures coincides both spatially Li et al. In line with these findings, Adk-tg mice express spontaneous recurrent electrographic seizures Li et al.
Conversely, therapeutic augmentation of the adenosine system is very effective in suppressing seizures Boison Together, these findings demonstrate that adenosine-deficiency and therefore deficient activation of A 1 Rs can be a direct cause for seizures. This conclusion supports the notion that methylxanthines have proconvulsant activity due to antagonizing the function of the endogenous anticonvulsant adenosine. Adenosine, acting via A 1 Rs, is not only an endogenous anticonvulsant of the brain, but also a powerful neuroprotectant Cunha ; Fredholm Thus, in addition to a proconvulsant role of A 1 R deficiency or increased adenosine clearance overexpression of ADK , these conditions lead to increased vulnerability to excitotoxic injury.
Consequently, A 1 R knockout mice are highly susceptible to seizure-induced Fedele et al. Pharmacological studies in a model of oxygen glucose deprivation OGD suggest that whereas A 1 Rs desensitize after prolonged agonist exposure, A 2A R mediated facilitation of glutamate release by endogenous adenosine remains fully operational under long-term OGD Sperlagh et al.
Thus, the inhibition of A 2A Rs might be a more effective approach to attenuate glutamatergic excitotoxicity than the stimulation of A 1 Rs Cunha Consequently, A 2A R antagonists are actively investigated clinically for their neuroprotective potential Chase et al.
Given the prominent role of adenosine as endogenous anticonvulsant and neuroprotectant, adenosine augmentation therapies AATs are highly effective in preventing seizures Boison Alternatives are focal AATs to avoid systemic side effects and to restore adenosinergic signalling within a localized area of adenosine dysfunction, which can be equated with an epileptogenic focus Li et al.
Strategies that have been explored include the implantation of adenosine-releasing silk-based polymers into the infrahippocampal fissure in kindled rats. Rats treated with these polymers were protected both from established seizures, as well as from developing epilepsy Szybala et al.
Likewise, rats with focal implants of adenosine-releasing encapsulated fibroblasts or ADK-deficient stem cells were protected from kindled seizures or kindling development, respectively Huber et al.
Stem-cell derived adenosine-releasing implants that were placed into the infrahippocampal fissure in mice were shown to suppress acute chemoconvulsant induced seizures with associated injury Ren et al. Together, these data demonstrate that focal re-constitution of adenosine signalling within an area of acquired adenosine dysfunction i.
There are, however, additional interactions that need to be considered: Whereas the proconvulsive activity of acute methylxanthines has long been recognized see above , the chronic dosing of caffeine has different effects. The effect was due to the combined effects of theophylline, to which caffeine is metabolized in brain, and caffeine itself but could not be ascribed to changes in A 1 and A 2A adenosine or GABA A receptors Johansson et al. Effect inversion of chronic adenosine receptor antagonists has also been described within the context of ischemic excitotoxicity de Mendonca et al.
Whereas acute methylxanthines generally aggravate ischemic injury, the chronic use of caffeine or of the A 1 R-selective antagonist DPCPX protects the brain from ischemic injury de Mendonca et al. The phenomenon of effect inversion of acute versus chronic caffeine has intensively been studied and has been explained by antagonism of an endogenous agonist that downregulates A 1 Rs without affecting gene transcription Jacobson et al.
Evidence for effect inversion by caffeine or adenosine receptor ligands has been obtained through changes in physiological outcome parameters such as susceptibility to seizures or to seizure- and ischemia- induced neuronal cell death Jacobson et al. Despite these clear physiological changes the molecular mechanisms behind this phenomenon appear to be more complex since upregulation of A 1 Rs as a consequence of chronic caffeine was not always observed Georgiev et al. Later studies have ruled out upregulation of A 1 Rs as a consequence of the long-term use of caffeine or theophylline in reasonably normal doses, indicating that upregulation of A 1 Rs is triggered only by excessively high or toxic doses of methylxanthines Svenningsson et al.
Thus, selected doses and durations of exposure and withdrawal, as well as A 2A R mediated effects see below might play an important role. This protective effect of acute caffeine can best be explained by antagonizing a seizure-induced surge of adenosine, which had experimentally been exacerbated by pharmacological disruption of adenosine clearance. In this model of SUDEP excessive seizure-induced concentrations of adenosine are thought to induce cardiac and respiratory failure by overstimulation of brainstem adenosine receptors, an effect that can be ameliorated by caffeine-induced blockade of these receptors Shen et al.
Whereas the anticonvulsant role of A 1 Rs is well established, newer findings suggest that A 2A Rs play an important role in modulating the susceptibility to seizures. Thus, A 2A R knockout mice are partially resistant to limbic seizures induced by chomoconvulsants or to seizures induced by ethanol withdrawal El Yacoubi et al. Interestingly, the attenuation of clonic pentylenetetrazole-induced seizures in A 2A R knockout mice could be mimicked in wild-type mice exposed to chronic caffeine 0.
However, A 2A R knockout mice under chronic caffeine were less protected from clonic seizures than water treated A 2A R KO mice, a conflicting result that was not further addressed El Yacoubi et al. Together, these findings indicate that the protective effects of chronic caffeine might best be explained by antagonizing the A 2A R and thus causing a state of decreased neuronal excitability; however, these studies also indicate a proconvulsive role of chronic caffeine under conditions, during which A 2A R-dependent signalling is abolished.
In contrast to adenosine receptors, which are affected by caffeine plasma concentrations attainable by normal human caffeine consumption, 10 to times higher concentrations are needed to inhibit GABA A Rs or PDE Fredholm et al. Ryanodine receptor RyR mediated calcium-induced calcium release CICR plays a key role in regulating intracellular calcium concentrations in epileptic conditions Pal et al. A possible role of free radicals in theophylline-induced seizures was recently suggested Gulati et al.
Seizures and mortality were attenuated by anti-oxidants melatonin, N-acetylcysteine and by nitric oxide NO synthase inhibitors L-NAME, 7-nitroindazole. Combination of anti-oxidant and NO-reducing treatments augmented the anticonvulsant effects of single treatments. Further, the authors found increased concentrations of malondialdehyde and NO metabolites in brain homogenates of mice with aminophylline-induced seizures; accumulation of these metabolites could be attenuated by melatonin or L-NAME pretreatment.
These studies suggest the contribution of free radicals in the mechanism of theophylline induced ictogenesis. Using whole-cell patch-clamp recordings on human TREK-1 channel expressing CHO cells, Harinath and Sikdar demonstrated reversible inhibition of the channels, and depolarization of the membrane potential, by caffeine and theophylline in a concentration-dependent manner Harinath and Sikdar Thus, inhibition of TREK-1 dependent membrane-depolarization may contribute to seizure generation by toxic doses of caffeine or theophylline.
Whereas inhibition of A 1 Rs by methylxanthines can directly contribute to ictogenesis and seizure spread, under certain conditions methylxanthines can also contribute to seizure suppression. First, this can be the case after chronic drug exposure leading effect inversion and alterations in gene expression Svenningsson et al.
Second, antagonism of A 2A Rs by methylxanthines may have direct anticonvulsant and neuroprotective consequences. A detailed understanding of the convulsant role of methylxanthines is of importance since many new drugs are in clinical trials that act on adenosine receptors. For example, in recent clinical trials conducted with the A 1 R antagonist rolofylline, which facilitates diuresis and preserves renal function in patients with acute heart failure AHF with renal impairment, the occurrence of seizures was described in some patients that were treated with higher doses of the drug Cotter et al.
This example demonstrates that caution is needed when evaluating the clinical use of new adenosine-related therapeutic agents; however, understanding the mechanisms involved in the adenosine-related control of seizure mechanisms will allow the safe use of novel drugs that act on new therapeutic principles.
National Center for Biotechnology Information , U. Author manuscript; available in PMC Jan 1. Author information Copyright and License information Disclaimer. The publisher's final edited version of this article is available at Handb Exp Pharmacol. See other articles in PMC that cite the published article. Abstract Clinical evidence, in particular the wide use of theophylline as bronchodilator, suggests that methylxanthines can cause seizures in patients without known underlying epilepsy. Experimental findings The preconvulsive potential of methylxanthines has been corroborated in countless animal studies that reach back to more than 35 years Roussinov et al.
Adenosine, seizures, and excitotoxicity Several potential mechanisms have been discussed that could explain the proconvulsive role of acute theophylline Yoshikawa Adenosine deficiency and seizure generation The role of adenosine as an endogenous regulator of hippocampal excitability was first recognized by Dunwiddie almost 30 years ago Dunwiddie Adenosine deficiency and excitotoxicity Adenosine, acting via A 1 Rs, is not only an endogenous anticonvulsant of the brain, but also a powerful neuroprotectant Cunha ; Fredholm Adenosine-based therapeutic approaches Given the prominent role of adenosine as endogenous anticonvulsant and neuroprotectant, adenosine augmentation therapies AATs are highly effective in preventing seizures Boison Acute versus chronic caffeine Whereas the proconvulsive activity of acute methylxanthines has long been recognized see above , the chronic dosing of caffeine has different effects.
A 1 and A 2A receptor-mediated actions Whereas the anticonvulsant role of A 1 Rs is well established, newer findings suggest that A 2A Rs play an important role in modulating the susceptibility to seizures. Free radicals in theophylline-induced seizures A possible role of free radicals in theophylline-induced seizures was recently suggested Gulati et al.
Causes, clinical features and consequences in 98 patients. Nutritional supplements, foods, and epilepsy: The equilibrative nucleoside transporter family, SLC Targeting histone deacetylase 2 in chronic obstructive pulmonary disease treatment. Expert Opin Ther Targets. Adenosine and its receptors: Adenosine kinase, epilepsy and stroke: The adenosine kinase hypothesis of epileptogenesis. While abnormal expression or function of GABA transporters has also been reported in nonabsence seizure models 9 , 10 , it is likely that mechanisms other than GAT-1 contribute to enhanced tonic GABA inhibition in absence epilepsy, although no evidence was found for several alternative mechanisms in this study.
Second, how the enhanced tonic inhibition actually influences the behavior of thalamocortical circuits to promote spike-and-wave discharges and to foster the clinical manifestations of absence seizures was not specifically addressed in this study.
While the authors speculate that persistent hyperpolarization of thalamocortical neurons should interrupt information flow through the thalamus, this does not necessarily account for the oscillatory behavior of these circuits in generating spike-and-wave discharges that are presumably central to absence seizures.
Future studies are needed to determine how too much inhibition promotes excitation in absence epilepsy. National Center for Biotechnology Information , U. Journal List Epilepsy Curr v. Copyright and License information Disclaimer. This article has been cited by other articles in PMC. GABAergic mechanisms in epilepsy.
Mutations affecting GABAergic signaling in seizures and epilepsy. Enhanced tonic GABA current in normotopic and hilar ectopic dentate granule cells after pilocarpine-induced status epilepticus. Trafficking of GABA A receptors, loss of inhibition, and a mechanism for pharmacoresistance in status epilepticus. Seizures and enhanced cortical GABAergic inhibition in two mouse models of human autosomal dominant nocturnal frontal lobe epilepsy.
Hosford DA, Wang Y. Neurons that fire together also conspire together: Is normal sleep circuitry hijacked to generate epilepsy? Hippocampal GABA transporter function in temporal lobe epilepsy. TXA caused a slight reduction in the rate and extent of current desensitization Supplemental Figure 3. However, desensitization in the presence of TXA was similar to that observed when glycine receptors were activated by a lower concentration of glycine alone.
This latter observation suggests that TXA does not directly modulate glycine receptor desensitization. To further determine whether TXA acts as a competitive antagonist, glycine concentration response plots were generated for currents recorded in the absence or presence of TXA Figure 2 B.
TXA 1 and 10 mM shifted the glycine concentration response plot to the right without reducing the maximal response. We next tested whether TXA inhibition of glycine receptors exhibited use or voltage dependence, as observed for noncompetitive antagonists that preferentially bind to the open state of the channel The degree of TXA inhibition was only slightly greater at negative holding potentials than positive holding potentials, as evidenced by the outward rectification of the current-voltage plot in the presence of TXA Figure 3 B.
These results are consistent with the interpretation that TXA is a competitive antagonist of glycine receptors. TXA inhibition of glycine receptors is not use or voltage dependent. The bar graph shows mean peak amplitude of the current recorded with and without coapplication of TXA. EACA, but not aprotinin, inhibits glycine receptors. EACA caused a rightward shift in the glycine concentration-response plot without reducing the maximal response Figure 4 B. EACA competitively inhibits glycine receptors, whereas aprotinin does not.
The effect of aprotinin on glycine receptor function was also investigated. Aprotinin was studied at lower concentrations, as its potency in terms of antifibrinolytic effect is greater than that of TXA or EACA TXA inhibits glycine receptors in spinal cord neurons.
Glycine receptors expressed in the spinal cord may exhibit pharmacological properties different from those of glycine receptors expressed in the cortex Therefore, we next investigated the effect of TXA on glycine receptors in spinal cord neurons.
In addition, cultures of spinal cord neurons offer the experimental advantage of a relatively high-throughput model to study the effects of TXA on postsynaptic glycinergic currents as well as currents activated by low and high concentrations of exogenous glycine The EC 50 of glycine in spinal cord neurons was determined to be To evaluate inhibition by TXA of glycine receptors under more physiologically relevant conditions, we studied glycinergic miniature inhibitory postsynaptic currents mIPSCs.
Application of strychnine abolished all glycinergic mIPSCs. Data for A — C were obtained from the same spinal cord neuron. In the absence of TXA, the amplitude of the glycine-evoked current was Also, the variance of the baseline current noise regulates network excitability Thus, we examined the effects of TXA on the baseline noise.
This rebound current was attributed to glycine receptors that were recovering from desensitization 52 , as a similar rebound phenomenon has been reported for competitive antagonists of GABA A receptors Thus, the current amplitude and the variance of the noise of the tonic glycine current were highly sensitive to TXA inhibition with the highest potency for glycine current evoked by low concentrations of agonist.
TXA, at clinical concentrations, inhibits current evoked by low concentrations of glycine. Isoflurane and propofol attenuate TXA inhibition of glycine receptors. TXA-associated seizures occur most frequently as patients emerge from general anesthesia in the early postoperative period 23 , 24 , 27 , Thus, we postulated that the prototypic general anesthetics isoflurane 60 and propofol 39 would attenuate TXA inhibition of glycine receptors.
Also, the benzodiazepine midazolam is frequently used as an anticonvulsant in the intensive care unit Hence, the effect of midazolam, which selectively upregulates GABA A receptor activity but has no effect on glycine receptors 62 , was studied as a negative control.
Isoflurane and propofol attenuate TXA inhibition of current evoked by a low concentration of glycine. TXA increases the frequency of seizure-like events and enhances evoked field potentials in cortical slices. Previous studies have shown that disinhibition, secondary to reduced glycine receptor function, can generate spontaneous epileptiform field potentials or seizure-like events SLEs in cortical slices 64 , We therefore studied whether TXA would increase the frequency of SLEs, as has been shown for other pro-epileptic drugs 66 — The bar graph shows that TXA increases the frequency but not the amplitude control: The proconvulsive properties of drugs can also be studied in cortical slices by recording field potentials in response to an excitatory electrical stimulus Evoked field responses represent the integrated electrical activity of a large number of neurons, reflecting a combination of synchronous synaptic potentials and action potentials This model provides useful information about the link between single neuron recordings and larger-scale neurophysiological signals such as electroencephalography Increases in the amplitude or area of field responses in cortical networks are correlated with increased excitatory synaptic drive Under baseline conditions, the evoked field response was characterized by an initial stimulation artefact, followed by a brief negatively directed peak Figure 9 B , as described previously The evoked response gradually returned to baseline after TXA washout.
These results suggest that TXA causes an increase in excitatory synaptic drive. Since glycine and GABA A receptors interact in a synchronized manner to regulate the excitability of neuronal networks, it is not possible to clearly delineate the specific contribution of each inhibitory receptor to the TXA-induced increase in network excitability.
Nevertheless, we attempted to probe the relative role of glycine receptors versus GABA A receptors by perfusing the slices with either strychnine or bicuculline in the absence and presence of TXA. Bicuculline alone increased the amplitude to Strychnine increased the amplitude to The amplitude of the evoked response was not affected further by TXA.
Isoflurane is more effective than propofol at reversing TXA enhancement of evoked field potentials in cortical slices. Since we showed that isoflurane and propofol attenuate TXA-mediated inhibition of glycine receptors, we sought to determine whether these anesthetics attenuate the increase in excitatory synaptic drive induced by TXA.
Perfusion of slices with isoflurane or propofol alone reduced both the amplitude and the area of the evoked field response Supplemental Figure 7 , as demonstrated previously 75 , Together these results suggest that isoflurane may be more effective than propofol at reversing TXA-induced increases in excitatory synaptic drive. However, the reversal of TXA-mediated excitability by anesthetics could be mediated by an attenuating effect on glycine receptors or GABA A receptors, by a combination of these inhibitory receptors, or by other anesthetic targets Isoflurane and propofol attenuate the enhancing effects of TXA on evoked field potentials in cortical slices.
Only receptors that are sensitive to clinically relevant concentrations of TXA are plausible mediators of the adverse effects of this drug.
Serum and CSF samples were obtained from patients who were undergoing repair of thoraco-abdominal pathology at certain times corresponding to procedural milestones. The average concentrations from the sample population are summarized in Figure 11 B. TXA concentrations measured in the serum and CSF of patients who underwent cardiopulmonary bypass and major vascular surgery.
The timeline at the bottom of the figure represents key surgical events. Surprisingly, the temporal profiles for TXA concentrations in the serum and CSF were substantially different, as indicated by the samples from a single patient Figure 11 A.
The peak concentration in the serum 1. To our knowledge, the study presented here is the first to identify glycine receptors as novel targets for inhibition by TXA and EACA, but not aprotinin. Because TXA is a competitive antagonist, inhibition mediated by this drug was expected to be highly dependent on the concentration of glycine applied, and this expectation was corroborated by the results.
We also show that TXA inhibition of glycine receptors activated by a low concentration of glycine EC 6 was reversed by isoflurane at clinically relevant concentrations. Propofol also reversed TXA-mediated glycine blockade, but only at concentrations 3-fold higher than those that occur during anesthesia Consistent with these results, TXA-induced enhancement of excitatory synaptic drive in cortical slices was more effectively reversed by isoflurane than by propofol.
Finally, we showed that the peak concentration of TXA in the CSF of patients undergoing major cardiovascular surgery A similar concentration of TXA increased the frequency of SLEs and enhanced evoked field responses in cortical slices, which suggests that TXA has proconvulsive properties. Inhibitors of glycine receptors are known to induce convulsions and proconvulsive behavior For example, strychnine causes myoclonic spasms 79 , twitching of muscles, convulsions, and hyperreactivity Genetic disorders characterized by reduced expression of glycine receptors cause hyperekplexia, convulsions, and startle disorders in infants In animals with naturally occurring mutations of the glycine receptor, the magnitude of the reduction in glycine receptor function directly correlates with the severity of the convulsive symptoms 81 , Thus, it is plausible that the reduction in function of these receptors caused by TXA leads to disinhibition and proconvulsive effects.
The demonstration that TXA attenuates tonic current is of great interest, since a reduction in tonic current enhances neuronal excitability 36 , Tonic current reduces neuronal excitability via two mechanisms. First, this type of current allows for the transfer of large quantities of negative charge, a process that hyperpolarizes the cell membrane Second, tonic conductance can attenuate the excitatory drive to generate action potentials by decreasing membrane resistance, thereby reducing the amplitude of excitatory postsynaptic potentials As anticipated for a competitive antagonist, the potency of TXA inhibition of glycine receptors was highly dependent on the concentration of agonist used in each experiment.
However, this difference in potency might also have been due, at least in part, to the subunit composition of glycine receptors. Synaptic glycinergic currents are generated by heteromeric receptors that are clustered at the postsynaptic sites Tonic glycinergic currents are mediated by homomeric receptors, which are located predominantly extrasynaptically
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Some patients describe epileptic seizures like an earthquake from within, About 10 seconds after the inhibition, the over-excitation spreads. PDI knockdown effectively inhibited seizure activities in both animal France; 10 mg/kg, i.p.) was administered and repeated, as needed. We found that pannexin-1 channel activation promoted seizure generation .. Furthermore, inhibiting Panx channels with 10Panx decreased.