Dian-Shi Wang

Tranexamic acid concentrations associated with human seizures inhibit glycine receptors

Antifibrinolytic drugs are widely used to reduce blood loss during surgery. One serious adverse effect of these drugs is convulsive seizures; however, the mechanisms underlying such seizures remain poorly understood. The antifibrinolytic drugs tranexamic acid (TXA) and ε-aminocaproic acid (EACA) are structurally similar to the inhibitory neurotransmitter glycine. Since reduced function of glycine receptors causes seizures, we hypothesized that TXA and EACA inhibit the activity of glycine receptors. Here we demonstrate that TXA and EACA are competitive antagonists of glycine receptors in mice. We also showed that the general anesthetic isoflurane, and to a lesser extent propofol, reverses TXA inhibition of glycine receptor-mediated current, suggesting that these drugs could potentially be used to treat TXA-induced seizures. Finally, we measured the concentration of TXA in the cerebrospinal fluid (CSF) of patients undergoing major cardiovascular surgery. Surprisingly, peak TXA concentration in the CSF occurred after termination of drug infusion and in one patient coincided with the onset of seizures. Collectively, these results show that concentrations of TXA equivalent to those measured in the CSF of patients inhibited glycine receptors. Furthermore, isoflurane or propofol may prevent or reverse TXA-induced seizures.

Memory Deficits Induced by Inflammation Are Regulated by α5-Subunit-Containing GABAA Receptors

SUMMARY Systemic inflammation causes learning and memory deficits through mechanisms that remain poorly understood. Here, we studied the pathogenesis of memory loss associated with inflammation and found that we could reverse memory deficits by pharmacologically inhibiting α5-subunit-containing γ-aminobutyric acid type A (α5GABAA) receptors and deleting the gene associated with the α5 subunit. Acute inflammation reduces long-term potentiation, a synaptic correlate of memory, in hippocampal slices from wild-type mice, and this reduction was reversed by inhibition of α5GABAA receptor function. A tonic inhibitory current generated by α5GABAA receptors in hippocampal neurons was increased by the key proinflammatory cytokine interleukin-1β through a p38 mitogen-activated protein kinase signaling pathway. Interleukin-1β also increased the surface expression of α5GABAA receptors in the hippocampus. Collectively, these results show that α5GABAA receptor activity increases during inflammation and that this increase is critical for inflammation-induced memory deficits.

Altered expression of δGABAA receptors in health and disease

γ-Aminobutyric acid type A receptors that contain the δ subunit (δGABAA receptors) are expressed in multiple types of neurons throughout the central nervous system, where they generate a tonic conductance that shapes neuronal excitability and synaptic plasticity. These receptors regulate a variety of important behavioral functions, including memory, nociception and anxiety, and may also modulate neurogenesis. Given their functional significance, δGABAA receptors are considered to be novel therapeutic targets for the treatment of memory dysfunction, pain, insomnia and mood disorders. These receptors are highly responsive to sedative-hypnotic drugs, general anesthetics and neuroactive steroids. A further remarkable feature of δGABAA receptors is that their expression levels are highly dynamic and fluctuate substantially during development and in response to physiological changes including stress and the reproductive cycle. Furthermore, the expression of these receptors varies in pathological conditions such as alcoholism, fragile X syndrome, epilepsy, depression, schizophrenia, mood disorders and traumatic brain injury. Such fluctuations in receptor expression have significant consequences for behavior and may alter responsiveness to therapeutic drugs. This review considers the alterations in the expression of δGABAA receptors associated with various states of health and disease and the implications of these changes.

Sustained increase in α5GABA A receptor function impairs memory after anesthesia

Many patients who undergo general anesthesia and surgery experience cognitive dysfunction, particularly memory deficits that can persist for days to months. The mechanisms underlying this postoperative cognitive dysfunction in the adult brain remain poorly understood. Depression of brain function during anesthesia is attributed primarily to increased activity of γ-aminobutyric acid type A receptors (GABA(A)Rs), and it is assumed that once the anesthetic drug is eliminated, the activity of GABA(A)Rs rapidly returns to baseline and these receptors no longer impair memory. Here, using a murine model, we found that a single in vivo treatment with the injectable anesthetic etomidate increased a tonic inhibitory current generated by α5 subunit-containing GABA(A)Rs (α5GABA(A)Rs) and cell-surface expression of α5GABA(A)Rs for at least 1 week. The sustained increase in α5GABA(A)R activity impaired memory performance and synaptic plasticity in the hippocampus. Inhibition of α5GABA(A)Rs completely reversed the memory deficits after anesthesia. Similarly, the inhaled anesthetic isoflurane triggered a persistent increase in tonic current and cell-surface expression of α5GABA(A)Rs. Thus, α5GABA(A)R function does not return to baseline after the anesthetic is eliminated, suggesting a mechanism to account for persistent memory deficits after general anesthesia.

Inhibition of learning and memory by general anesthetics

PurposeToday’s general anesthetics were developed empirically according to their ability to produce memory blockade, analgesia, immobility, and unconsciousness. Thus, a major outstanding question remains: How do anesthetics produce their desirable behavioural end points at the molecular level? Understanding the mechanisms underlying memory blockade is of particular importance, because some patients experience the unexpected recall of events during anesthesia while others experience persistent memory deficits in the postoperative period. This review provides a brief summary of the acute memory-blocking properties of general anesthetics and the neuronal substrates that most likely contribute to memory loss.Principal findingsStudies in human volunteers and laboratory animals have shown that the memory-blocking properties of general anesthetics depend on the specific drug, the dose, the type of memory, and the experimental paradigm, as well as the species and age of the experimental subject. The cellular substrates of memory blockade include an increase in neuronal inhibition by γ-aminobutyric acid subtype A receptors, a decrease in excitatory glutamatergic neurotransmission, and alterations in synaptic plasticity.ConclusionsAnesthetics target different receptors and brain regions to modify the various forms of memory. In the hippocampus, extrasynaptic γ-aminobutyric acid subtype A receptors may play a particularly important role. Knowledge regarding the molecular basis of memory blockade may help to address memory disorders associated with the anesthetic state.RésuméObjectifLes anesthésiques généraux actuels ont été mis au point empiriquement en se fondant sur leur capacité à bloquer la mémoire ainsi qu’à provoquer l’analgésie, l’immobilité et l’inconscience. En raison de ce développement empirique, une question cruciale demeure sans réponse: comment les anesthésiques produisent-ils leurs effets désirables sur le comportement au niveau moléculaire? La compréhension des mécanismes sous-jacents au blocage de la mémoire est particulièrement importante, étant donné que certains patients se souviennent de manière imprévue d’événements ayant eu lieu pendant qu’ils étaient sous anesthésie, alors que d’autres souffrent de troubles de mémoire persistants en période postopératoire. Ce compte-rendu présente brièvement les propriétés des anesthésiques généraux sur le blocage aigu de la mémoire ainsi que les substrats neuronaux qui contribuent très probablement à la perte de mémoire.Constatations principalesLes études réalisées chez des volontaires humains et des animaux de laboratoire ont montré que les propriétés des anesthésiques généraux sur le blocage de la mémoire sont dépendantes du médicament en question, de sa dose, du type de mémoire, du paradigme expérimental, ainsi que de l’espèce et de l’âge du sujet soumis à l’expérience. Les substrats cellulaires de blocage de la mémoire comprennent une augmentation de l’inhibition neuronale des récepteurs de l’acide γ-amino-butyrique de type A (GABAA), une diminution de la neurotransmission glutamatergique excitatrice, et des modifications de la plasticité synaptique.ConclusionLes anesthésiques ciblent différents récepteurs et régions du cerveau pour modifier les diverses formes de mémoire. Dans l’hippocampe, les récepteurs extrasynaptiques de l’acide γ-amino-butyrique de type A pourraient jouer un rôle particulièrement important. Des connaissances concernant la base moléculaire du blocage de la mémoire pourraient nous permettre de mieux comprendre et traiter les troubles de la mémoire associés à l’état d’anesthésie.

Tranexamic acid-associated seizures: Causes and treatment.

Antifibrinolytic drugs are routinely used worldwide to reduce the bleeding that results from a wide range of hemorrhagic conditions. The most commonly used antifibrinolytic drug, tranexamic acid, is associated with an increased incidence of postoperative seizures. The reported increase in the frequency of seizures is alarming, as these events are associated with adverse neurological outcomes, longer hospital stays, and increased in‐hospital mortality. However, many clinicians are unaware that tranexamic acid causes seizures. The goal of this review is to summarize the incidence, risk factors, and clinical features of these seizures. This review also highlights several clinical and preclinical studies that offer mechanistic insights into the potential causes of and treatments for tranexamic acid–associated seizures. This review will aid the medical community by increasing awareness about tranexamic acid–associated seizures and by translating scientific findings into therapeutic interventions for patients. ANN NEUROL 2016;79:18–26

Acutely increasing δGABA(A) receptor activity impairs memory and inhibits synaptic plasticity in the hippocampus.

Extrasynaptic γ-aminobutyric acid type A (GABAA) receptors that contain the δ subunit (δGABAA receptors) are expressed in several brain regions including the dentate gyrus (DG) and CA1 subfields of the hippocampus. Drugs that increase δGABAA receptor activity have been proposed as treatments for a variety of disorders including insomnia, epilepsy and chronic pain. Also, long-term pretreatment with the δGABAA receptor–preferring agonist 4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-3-ol (THIP) enhances discrimination memory and increases neurogenesis in the DG. Despite the potential therapeutic benefits of such treatments, the effects of acutely increasing δGABAA receptor activity on memory behaviors remain unknown. Here, we studied the effects of THIP (4 mg/kg, i.p.) on memory performance in wild-type (WT) and δGABAA receptor null mutant (Gabrd−/−) mice. Additionally, the effects of THIP on long-term potentiation (LTP), a molecular correlate of memory, were studied within the DG and CA1 subfields of the hippocampus using electrophysiological recordings of field potentials in hippocampal slices. The results showed that THIP impaired performance in the Morris water maze, contextual fear conditioning and object recognition tasks in WT mice but not Gabrd−/− mice. Furthermore, THIP inhibited LTP in hippocampal slices from WT but not Gabrd−/− mice, an effect that was blocked by GABAA receptor antagonist bicuculline. Thus, acutely increasing δGABAA receptor activity impairs memory behaviors and inhibits synaptic plasticity. These results have important implications for the development of therapies aimed at increasing δGABAA receptor activity.

γ-aminobutyric acid type A receptors that contain the δ subunit promote memory and neurogenesis in the dentate gyrus

Extrasynaptic γ‐aminobutyric acid type A receptors that contain the δ subunit (δGABAA receptors) are highly expressed in the dentate gyrus (DG) subfield of the hippocampus, where they generate a tonic conductance that regulates neuronal activity. GABAA receptor‐dependent signaling regulates memory and also facilitates postnatal neurogenesis in the adult DG; however, the role of the δGABAA receptors in these processes is unclear. Accordingly, we sought to determine whether δGABAA receptors regulate memory behaviors, as well as neurogenesis in the DG.

Inflammation Increases Neuronal Sensitivity to General Anesthetics.

Background:Critically ill patients with severe inflammation often exhibit heightened sensitivity to general anesthetics; however, the underlying mechanisms remain poorly understood. Inflammation increases the number of &ggr;-aminobutyric acid type A (GABAA) receptors expressed on the surface of neurons, which supports the hypothesis that inflammation increases up-regulation of GABAA receptor activity by anesthetics, thereby enhancing the behavioral sensitivity to these drugs. Methods:To mimic inflammation in vitro, cultured hippocampal and cortical neurons were pretreated with interleukin (IL)-1&bgr;. Whole cell patch clamp methods were used to record currents evoked by &ggr;-aminobutyric acid (GABA) (0.5 &mgr;M) in the absence and presence of etomidate or isoflurane. To mimic inflammation in vivo, mice were treated with lipopolysaccharide, and several anesthetic-related behavioral endpoints were examined. Results:IL-1&bgr; increased the amplitude of current evoked by GABA in combination with clinically relevant concentrations of either etomidate (3 &mgr;M) or isoflurane (250 &mgr;M) (n = 5 to 17, P < 0.05). Concentration–response plots for etomidate and isoflurane showed that IL-1&bgr; increased the maximal current 3.3-fold (n = 5 to 9) and 1.5-fold (n = 8 to 11), respectively (P < 0.05 for both), whereas the half-maximal effective concentrations were unchanged. Lipopolysaccharide enhanced the hypnotic properties of both etomidate and isoflurane. The immobilizing properties of etomidate, but not isoflurane, were also increased by lipopolysaccharide. Both lipopolysaccharide and etomidate impaired contextual fear memory. Conclusions:These results provide proof-of-concept evidence that inflammation increases the sensitivity of neurons to general anesthetics. This increase in anesthetic up-regulation of GABAA receptor activity in vitro correlates with enhanced sensitivity for GABAA receptor–dependent behavioral endpoints in vivo.

Sleep and Anesthesia: Neural Correlates in Theory and Experiment

The book gives an overview of theoretical and experimental techniques in sleep and anaesthesia.