scholarly journals Excitatory GABAergic signalling is associated with benzodiazepine resistance in status epilepticus

Brain ◽  
2019 ◽  
Vol 142 (11) ◽  
pp. 3482-3501 ◽  
Author(s):  
Richard J Burman ◽  
Joshua S Selfe ◽  
John Hamin Lee ◽  
Maurits van den Berg ◽  
Alexandru Calin ◽  
...  
Keyword(s):  
Status Epilepticus ◽  
Synaptic Transmission ◽  
Gabaa Receptor ◽  
Current Management ◽  
Seizure Duration ◽  
Clinical Indicator ◽  
Clinical Challenge

Benzodiazepine-resistant status epilepticus is an ongoing clinical challenge. Burman et al. show that longer seizure duration is a useful clinical indicator of benzodiazepine resistance, and that resistance is caused by changes in GABAA receptor-mediated synaptic transmission. The findings could help optimise current management protocols.

Hemoglobin metabolites mimic benzodiazepines and are possible mediators of hepatic encephalopathy

Blood ◽  
2003 ◽  
Vol 102 (4) ◽  
pp. 1525-1528 ◽  
Author(s):  
Brian J. Ruscito ◽  
Neil L. Harrison
Keyword(s):  
Cognitive Impairment ◽  
Hepatic Encephalopathy ◽  
Synaptic Transmission ◽  
Liver Failure ◽  
Gabaa Receptor ◽  
Protoporphyrin Ix ◽  
Aminobutyric Acid ◽  
Endogenous Ligands ◽  
Inhibitory Synaptic Transmission ◽  
Clinical Observations

Abstract Liver failure is often accompanied by cognitive impairment and coma, a syndrome known as hepatic encephalopathy (HE). The administration of flumazenil, a benzodiazepine (BZ) antagonist, is effective in reversing the symptoms of HE in many patients. These clinical observations gave rise to notions of an endogenous BZ-like mechanism in HE, but to date no viable candidate compounds have been characterized. We show here that the hemoglobin (Hb) metabolites hemin and protoporphyrin IX (PPIX) interact with the BZ site on the γ-aminobutyric acid (GABAA) receptor and enhance inhibitory synaptic transmission in a manner similar to diazepam and zolpidem. This finding suggests that hemin and PPIX are neuroactive porphyrins capable of acting as endogenous ligands for the central BZ site. The accumulation of these porphyrins under pathophysiologic conditions provides a potentially novel mechanism for the central manifestations of HE.

Postsynaptic mechanisms underlying long-term depression of GABAergic transmission in neurons of the deep cerebellar nuclei

1996 ◽  
Vol 76 (1) ◽  
pp. 59-68 ◽  
Author(s):  
W. Morishita ◽  
B. R. Sastry
Keyword(s):  
Synaptic Transmission ◽  
Gabaa Receptor ◽  
Cell Voltage ◽  
Cerebellar Nuclei ◽  
Neuronal Membrane ◽  
Gamma Aminobutyric Acid ◽  
Deep Cerebellar Nuclei ◽  
Long Term Depression ◽  
In Cells

1. The mechanisms underlying long-term depression (LTD) of gamma-aminobutyric acid-A (GABAA) receptor-mediated synaptic transmission induced by 10-Hz stimulation of the inhibitory afferents were investigated using perforated and whole cell voltage-clamp recordings from neurons of the deep cerebellar nuclei (DCN). 2. LTD of inhibitory postsynaptic currents (IPSCs) was reliably induced when the 10-Hz stimulation was delivered under current-clamp conditions where the postsynaptic neuronal membrane was allowed to depolarize. 3. Currents elicited by local applications of the GABAA receptor agonist, 4,5,6,7-tetrahydroisoxazolo [5,4-c]pyridin-3-ol hydrochloride (THIP) were also depressed during LTD. 4. LTD could be induced heterosynaptically and did not require the activation of GABAA receptors during the 10-Hz stimulation. 5. In cells loaded with QX-314 and superfused with media containing 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) and 2-amino-5-phosphonovaleric acid (APV), a series of depolarizing pulses (50 mV, 200 ms) induced a sustained depression of the IPSC. However, this was not observed in cells recorded with high bis-(o-aminophenoxy)-N,N,N',N'-tetraacetic acid (BAPTA)-containing pipette solutions or when they were exposed to the L-type Ca2+ channel antagonist, nitrendipine. 6. The 10-Hz-induced LTD was also inhibited by BAPTA and was significantly reduced when DCN cells were loaded with microcystin LR or treated with okadaic acid, both inhibitors of protein phosphatases. 7. These results indicate that increases in postsynaptic [Ca2+] and phosphatase activity can reduce the efficacy of GABAA receptor-mediated synaptic transmission.

Tranexamic Acid Impairs γ-Aminobutyric Acid Receptor Type A–mediated Synaptic Transmission in the Murine Amygdala

2014 ◽  
Vol 120 (3) ◽  
pp. 639-649 ◽  
Author(s):  
Stephan Kratzer ◽  
Hedwig Irl ◽  
Corinna Mattusch ◽  
Martina Bürge ◽  
Jörg Kurz ◽  
...  
Keyword(s):  
Patch Clamp ◽  
Synaptic Transmission ◽  
Tranexamic Acid ◽  
Gabaa Receptor ◽  
Type A ◽  
Aminobutyric Acid ◽  
Receptor Type ◽  
Voltage Sensitive Dye ◽  
Acid Receptor ◽  
Neuronal Excitation

Abstract Background: Tranexamic acid (TXA) is commonly used to reduce blood loss in cardiac surgery and in trauma patients. High-dose application of TXA is associated with an increased risk of postoperative seizures. The neuronal mechanisms underlying this proconvulsant action of TXA are not fully understood. In this study, the authors investigated the effects of TXA on neuronal excitability and synaptic transmission in the basolateral amygdala. Methods: Patch clamp recordings and voltage-sensitive dye imaging were performed in acute murine brain slices. Currents through N-methyl-d-aspartate, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid, and γ-aminobutyric acid receptor type A (GABAA) receptors were recorded. GABAA receptor–mediated currents were evoked upon electrical stimulation or upon photolysis of caged GABA. TXA was applied at different concentrations. Results: Voltage-sensitive dye imaging demonstrates that TXA (1 mM) reversibly enhances propagation of neuronal excitation (mean ± SEM, 129 ± 6% of control; n = 5). TXA at concentrations of 0.1, 0.3, 1, 5, or 10 mM led to a dose-dependent reduction of GABAA receptor–mediated currents in patch clamp recordings. There was no difference in the half-maximal inhibitory concentration for electrically (0.76 mM) and photolytically (0.84 mM) evoked currents (n = 5 to 9 for each concentration), and TXA did not affect the paired-pulse ratio of GABAA receptor–mediated currents. TXA did not impact glutamatergic synaptic transmission. Conclusions: This study clearly demonstrates that TXA enhances neuronal excitation by antagonizing inhibitory GABAergic neurotransmission. The results provide evidence that this effect is mediated via postsynaptic mechanisms. Because GABAA receptor antagonists are known to promote epileptiform activity, this effect might explain the proconvulsant action of TXA.

scholarly journals Characteristics of Patient with Status Epilepticus at the Emergency Department of Sanglah General Hospital

2021 ◽  
Vol 8 (12) ◽  
pp. 211-217
Author(s):  
Maria Oktaviany Gabur ◽  
I Wayan Widyantara ◽  
Anna M.G. Sinardja
Keyword(s):  
Status Epilepticus ◽  
General Hospital ◽  
Medical Records ◽  
Seizure Activity ◽  
Initial Therapy ◽  
Platelet Volume ◽  
Seizure Duration ◽  
Neutrophil Lymphocyte Ratio ◽  
Intravenous Diazepam ◽  
Patient’S Outcome

Introduction: Status epilepticus is a neurological condition caused by a failure of body mechanism to terminate the seizures or the onset of abnormal seizure activity resulting in prolonged seizure’s duration for more than five minutes. The available research data on status epilepticus in Indonesia is still limited. The purpose of this study was to determine the profile of patients with status epilepticus at Sanglah General Hospital from 2020 to 2021. Methods: This was a descriptive study with a retrospective approach. The study populations were patients with status epilepticus who were treated at Sanglah General Hospital in 2019-2020 who had no missing data in the medical records. Results: There were 117 patients with status epilepticus, 63 males (53.8%) and 54 females (46.2%). There are 41 patients>60 years (35%), general onset in 63 patients (53.8%), and focal onset in 54 patients (46.2%). Etiology from cerebral was 68 patients (58.1%), followed by metabolic in 28 patients (23.9%). The most common OAE therapy was phenytoin (86.3%) and the longest length of stay status epilepticus patients was 8 days (55.6%). Patients with status epilepticus had leukocytosis (73.5%), increased NLR (66.7%), and decreased mean platelet volume (53.8%). Conclusion: The highest incidence of status epilepticus is in women, above 60 years, general onset type of seizure, and etiology from cerebral. Initial therapy in 117 patients was intravenous diazepam followed by phenytoin for maintenance. NLR increased in most of the patients showing signs of inflammation which further worsened the patient's outcome with a mortality rate of 47%. Keywords: Status epilepticus, seizure duration, anticonvulsant, neutrophil-lymphocyte ratio.

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