Flurothyl
Convulsants
Seizures
Norepinephrine-deficient mice have increased susceptibility to seizure-inducing stimuli. (1/33)
Several lines of evidence suggest that norepinephrine (NE) can modulate seizure activity. However, the experimental methods used in the past cannot exclude the possible role of other neurotransmitters coreleased with NE from noradrenergic terminals. We have assessed the seizure susceptibility of genetically engineered mice that lack NE. Seizure susceptibility was determined in the dopamine beta-hydroxylase null mutant (Dbh -/-) mouse using four different convulsant stimuli: 2,2,2-trifluroethyl ether (flurothyl), pentylenetetrazol (PTZ), kainic acid, and high-decibel sound. Dbh -/- mice demonstrated enhanced susceptibility (i.e., lower threshold) compared with littermate heterozygous (Dbh +/-) controls to flurothyl, PTZ, kainic acid, and audiogenic seizures and enhanced sensitivity (i.e., seizure severity and mortality) to flurothyl, PTZ, and kainic acid. c-Fos mRNA expression in the cortex, hippocampus (CA1 and CA3), and amygdala was increased in Dbh -/- mice in association with flurothyl-induced seizures. Enhanced seizure susceptibility to flurothyl and increased seizure-induced c-fos mRNA expression were reversed by pretreatment with L-threo-3, 4-dihydroxyphenylserine, which partially restores the NE content in Dbh -/- mice. These genetically engineered mice confirm unambiguously the potent effects of the noradrenergic system in modulating epileptogenicity and illustrate the unique opportunity offered by Dbh -/- mice for elucidating the pathways through which NE can regulate seizure activity. (+info)Differential modulatory actions of the volatile convulsant flurothyl and its anesthetic isomer at inhibitory ligand-gated ion channels. (2/33)
A challenge for theories of general anesthesia is the existence of compounds predicted to be anesthetics but which, instead, do not produce anesthesia and often elicit other behavioral effects such as convulsions. This study focused on flurothyl (bis[2,2, 2-trifluoroethyl] ether), a potent volatile convulsant, and its anesthetic isomer, 'iso-flurothyl' (1,1,1,3,3, 3-hexafluoro-2-methoxypropane). The effects of flurothyl and iso-flurothyl were studied using the whole-cell patch-clamp technique on agonist-activated chloride currents in human GABA(A), glycine, and GABA(C) rho(1) receptors expressed in HEK 293 cells. GABA(A) and glycine receptors are promising molecular targets for the actions of inhaled ether general anesthetics. Flurothyl acted as a non-competitive antagonist at GABA(A) alpha(2)beta(1) and alpha(2)beta(1)gamma(2s) receptors, but had no effect at glycine alpha(1) receptors. Flurothyl had biphasic actions on GABA responses at GABA(C) rho(1) receptors. In contrast, iso-flurothyl enhanced ('potentiated') submaximal agonist responses at GABA(A) and glycine receptors, but had no effect on GABA responses at GABA(C) rho(1) receptors. Point mutations in GABA(A) and glycine receptor subunits, which have been previously shown to abolish potentiation of agonist responses by the ether anesthetics enflurane and isoflurane, also ablated potentiation of agonist responses by iso-flurothyl. These same mutations in the GABA(A) receptor had only modest effects on the inhibitory actions of flurothyl. GABA(A) receptors with mutations conferring insensitivity to antagonism by picrotoxin were still inhibited by flurothyl, suggesting that picrotoxin and flurothyl antagonize GABA responses by distinct sites or mechanisms of action. In summary, antagonism of GABA(A) receptors is likely to account for the convulsant effects of flurothyl, while the general anesthetic actions of iso-flurothyl, like those of other ether anesthetics, may be related to positive modulation of GABA(A) and/or glycine receptors. (+info)Effects of volatile solvents on recombinant N-methyl-D-aspartate receptors expressed in Xenopus oocytes. (3/33)
1. We have previously shown that toluene dose-dependently inhibits recombinant N-methyl-D-aspartate (NMDA) receptors at micromolar concentrations. This inhibition was rapid, almost complete and reversible. The NR1/2B combination was the most sensitive receptor subtype tested with an IC(50) value for toluene of 0.17 mM. 2. We now report on the effects of other commonly abused solvents (benzene, m-xylene, ethylbenzene, propylbenzene, 1,1,1-trichlorethane (TCE) and those of a convulsive solvent, 2,2,2-trifluoroethyl ether (flurothyl), on NMDA-induced currents measured in XENOPUS oocytes expressing NR1/2A or NR1/2B receptor subtypes. 3. All of the alkylbenzenes and TCE produced a reversible inhibition of NMDA-induced currents that was dose- and subunit-dependent. The NR1/2B receptor subtype was several times more sensitive to these compounds than the NR1/2A subtype. 4. The convulsant solvent flurothyl had no effect on NMDA responses in oocytes but potently inhibited ion flux through recombinant GABA receptors expressed in oocytes. 5. Overall, these results suggest that abused solvents display pharmacological selectivity and that NR1/2B NMDA receptors may be an important target for the actions of these compounds on the brain. (+info)Abnormal morphological and functional organization of the hippocampus in a p35 mutant model of cortical dysplasia associated with spontaneous seizures. (4/33)
Cortical dysplasia is a major cause of intractable epilepsy in children. However, the precise mechanisms linking cortical malformations to epileptogenesis remain elusive. The neuronal-specific activator of cyclin-dependent kinase 5, p35, has been recognized as a key factor in proper neuronal migration in the neocortex. Deletion of p35 leads to severe neocortical lamination defects associated with sporadic lethality and seizures. Here we demonstrate that p35-deficient mice also exhibit dysplasia/ heterotopia of principal neurons in the hippocampal formation, as well as spontaneous behavioral and electrographic seizures. Morphological analyses using immunocytochemistry, electron microscopy, and intracellular labeling reveal a high degree of abnormality in dentate granule cells, including heterotopic localization of granule cells in the molecular layer and hilus, aberrant dendritic orientation, occurrence of basal dendrites, and abnormal axon origination sites. Dentate granule cells of p35-deficient mice also demonstrate aberrant mossy fiber sprouting. Field potential laminar analysis through the dentate molecular layer reflects the dispersion of granule cells and the structural reorganization of this region. Similar patterns of cortical disorganization have been linked to epileptogenesis in animal models of chronic seizures and in human temporal lobe epilepsy. The p35-deficient mouse may therefore offer an experimental system in which we can dissect out the key morphological features that are causally related to epileptogenesis. (+info)Reduced neurogenesis after neonatal seizures. (5/33)
Although neonatal seizures are quite common, there is controversy regarding their consequences. Despite considerable evidence that seizures may cause less cell loss in young animals compared with mature animals, there are nonetheless clear indications that seizures may have other potentially deleterious effects. Because it is known that seizures in the mature brain can increase neurogenesis in the hippocampus, we studied the extent of neurogenesis in the granule cell layer of the dentate gyrus over multiple time points after a series of 25 flurothyl-induced seizures administered between postnatal day 0 (P0) and P4. Rats with neonatal seizures had a significant reduction in the number of the thymidine analog 5-bromo-2'-deoxyuridine-5'-monophosphate- (BrdU) labeled cells in the dentate gyrus and hilus compared with the control groups when the animals were killed either 36 hr or 2 weeks after the BrdU injections. The reduction in BrdU-labeled cells continued for 6 d after the last seizure. BrdU-labeled cells primarily colocalized with the neuronal marker neuron-specific nuclear protein and rarely colocalized with the glial cell marker glial fibrillary acidic protein, providing evidence that a very large percentage of the newly formed cells were neurons. Immature rats subjected to a single seizure did not differ from controls in number of BrdU-labeled cells. In comparison, adult rats undergoing a series of 25 flurothyl-induced seizures had a significant increase in neurogenesis compared with controls. This study indicates that, after recurrent seizures in the neonatal rat, there is a reduction in newly born granule cells. (+info)Genetic comparison of seizure control by norepinephrine and neuropeptide Y. (6/33)
Epilepsy is a disease of neuronal hyperexcitability, and pharmacological and genetic studies have identified norepinephrine (NE) and neuropeptide Y (NPY) as important endogenous regulators of neuronal excitability. Both transmitters signal through G-protein-coupled receptors, are expressed either together or separately, and are abundant in brain regions implicated in seizure generation. NPY knock-out (NPY KO) and dopamine beta-hydroxylase knock-out (DBH KO) mice that lack NE are susceptible to seizures, and agonists of NE and NPY receptors protect against seizures. To examine the relative contributions of NE and NPY to neuronal excitability, we tested Dbh;Npy double knock-out (DKO) mice for seizure sensitivity. In general, DBH KO mice were much more seizure-sensitive than NPY KO mice and had normal NPY expression, demonstrating that an NPY deficiency did not contribute to the DBH KO seizure phenotype. DKO mice were only slightly more sensitive than DBH KO mice to seizures induced by kainic acid, pentylenetetrazole, or flurothyl, although DKO mice were uniquely prone to handling-induced seizures. NPY contributed to the seizure phenotype of DKO mice at high doses of convulsant agents and advanced stages of seizures. These data suggest that NE is a more potent endogenous anticonvulsant than NPY, and that NPY has the greatest contribution under conditions of extreme neuronal excitability. (+info)The effect of convulsions induced by flurothyl on ribonucleic acid synthesis in rat cerebral cortex during the recovery phase. (7/33)
The effect of convulsions, induced by flurothyl, on RNA synthesis in purified unfractionated nuclei and the cytoplasm of rat cerebral cortex was studied by using a double-label technique involving injection of [3H]- and [14C]-orotate intracisternally. 2. Intact RNA was extracted in 80% yield by an enzymic method by using a proteinase in the presence of sodium dodecyl sulphate followed by deoxyribonuclease. Electrophoresis on 1.5% polyacrylamide-0.5% agarose gels revealed the presence of giant nuclear RNA of size up to approx. 300X 10(6) daltons and mRNA of maximal mol.wt. 9 X 10(6)-16 X 10(6). 3. Nuclear RNA synthesis was decreased to 27% in the first 15 min after convulsions but rapidly increased, so that at 1 1/2 h it was 124% of the control, and at 6 h 147%. 4. Labelling of cytoplasmic RNA was decreased to 15% at 15 min after convulsions but had not recovered to control values by 6 h. 5. Analysis of radioactive gel patterns and the 3H/14C ratio at six time-points (15 min-6h) showed that the major effect was inhibition of the processing of heterogeneous nuclear RNA resulting in a sharp decline in the export of newly synthesized RNA from the nucleus. 6. Cytoplasmic RNA patterns indicated that specific messengers were synthesized at different times during the recovery of the cell after convulsions. (+info)Regional neural activity within the substantia nigra during peri-ictal flurothyl generalized seizure stages. (8/33)
Structures responsible for the onset, propagation, and cessation of generalized seizures are not known. Lesion and microinfusion studies suggest that the substantia nigra pars reticulata (SNR) seizure-controlling network could play a key role. However, the expression of neural activity within the SNR and its targets during discrete pre- and postictal periods has not been investigated. In rats, we used flurothyl to induce generalized seizures over a controlled time period and 2-deoxyglucose autoradiography mapping technique. Changes in neural activity within the SNR were region-specific. The SNRposterior was selectively active during the pre-clonic period and may represent an early gateway to seizure propagation. The SNRanterior and superior colliculus changed their activity during progression to tonic-clonic seizure, suggesting the involvement in coordinated regional activity that results in inhibitory effects on seizures. The postictal suppression state was correlated with changes in the SNR projection targets, specifically the pedunculopontine tegmental nucleus and superior colliculus. (+info)Flurothyl, also known as Nelson's fluid or induction agent, is a chemical compound with the formula C5H4F6O. It is a colorless liquid that is volatile and has a sweetish odor. In medicine, it was historically used as a rapid-acting inhalational general anesthetic, but its use has been largely discontinued due to safety concerns, including the risk of seizures and cardiac arrest. Flurothyl works by sensitizing the brain to carbon dioxide, leading to a loss of consciousness. It is still used in research settings to study seizure disorders and anesthetic mechanisms.
Convulsants are substances or agents that can cause seizures or convulsions. These can be medications, toxins, or illnesses that lower the seizure threshold and lead to abnormal electrical activity in the brain, resulting in uncontrolled muscle contractions and relaxation. Examples of convulsants include bromides, strychnine, organophosphate pesticides, certain antibiotics (such as penicillin or cephalosporins), and alcohol withdrawal. It is important to note that some medications used to treat seizures can also have convulsant properties at higher doses or in overdose situations.
A seizure is an uncontrolled, abnormal firing of neurons (brain cells) that can cause various symptoms such as convulsions, loss of consciousness, altered awareness, or changes in behavior. Seizures can be caused by a variety of factors including epilepsy, brain injury, infection, toxic substances, or genetic disorders. They can also occur without any identifiable cause, known as idiopathic seizures. Seizures are a medical emergency and require immediate attention.
Flurothyl
Theories of general anaesthetic action
2,2,3,3-Tetrafluoropropyl trifluoromethyl ether
Isoflurothyl
Methylazoxymethanol acetate
Max Fink
Convulsant
Ventromedial nucleus of the hypothalamus
Inhalational anesthetic
Halogenated ether
GABAA receptor negative allosteric modulator
Causes of seizures
List of MeSH codes (D02)
C4H4F6O
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Tonic-clonic flurothyl-induced seizures2
- In PN 15 rats, irrespective of the stimulation site within the SNR, bilateral stimulations of the SNR produced anticonvulsant effects against both clonic and tonic-clonic flurothyl-induced seizures, while unilateral stimulation was without effect. (elsevierpure.com)
- SNR microinfusions of zolpidem did not alter the threshold to tonic-clonic flurothyl-induced seizures. (elsevierpure.com)
Experimented with flurothyl to induce seizures1
- In 1953, the Maryland pharmacologist J. C. Krantz experimented with flurothyl to induce seizures in psychiatric patients as an alternative to ECT. (wikipedia.org)
Seizures10
- Equal degrees of EEG slow wave increases were recorded in flurothyl and electrical induced seizures. (wikipedia.org)
- Flurothyl induced seizures were deemed clinically equal to electrical seizures with lesser effects on cognition and memory. (wikipedia.org)
- AS model mice kindled similarly to wild-type mice, but they displayed a markedly increased sensitivity to flurothyl-, kainic acid-, and hyperthermia-induced seizures measured a month later during retest. (jci.org)
- The rats were stimulated with continuous constant current pulses (130 Hz) and simultaneously challenged with flurothyl to induce seizures. (elsevierpure.com)
- In adult rats, we determined the effects of bilateral zolpidem (an agonist of the BZD 1 receptor site) microinfusions in the anterior or in the posterior SNR (SNR(anterior) or SNR(posterior), respectively) on flurothyl-induced clonic and tonic-clonic seizures. (elsevierpure.com)
- Our data demonstrate that the BZD 1 binding sites are involved in the SNR control of flurothyl seizures in adult and PN 15 male rats. (elsevierpure.com)
- Methods: We explored the spatial-temporal dynamics of SD and epileptic activity across layers of the rat barrel cortex using direct current silicone probe recordings during flurothyl-induced seizures. (johnshopkins.edu)
- Results: Spreading depolarization occurred in half of the flurothyl-evoked seizures. (johnshopkins.edu)
- Using a flurothyl seizure model, AS model mice responded similarly to their WT littermates during the initial seizure inductions and the subsequent week of kindling, but at a re-test a month later, the AS model mice demonstrated a markedly increased sensitivity to flurothyl-induced seizures compared to the WT mice. (investmentvaluefinders.com)
- When the mice were given acute CBD (100 mg/kg), the researchers were surprised to see that it had little-to-no effect on the flurothyl-induced seizure threshold or on the body temperature for onset of the hyperthermia-included seizures. (investmentvaluefinders.com)
Rats1
- The influence of hyperthermia and hypothermia on epileptic brain damage was studied in rats, in which status epilepticus was induced by flurothyl. (hyperthermicwellness.com)
Model mice1
- Here, we implemented the flurothyl kindling and retest paradigm in AS model mice to assess epileptogenesis and to gain mechanistic insights owed to loss of maternal Ube3a. (jci.org)
Results2
- Four random assignment treatment studies found the clinical results for flurothyl to be as effective as those of ECT. (wikipedia.org)
- The clinical results were the same as with inhaled flurothyl. (wikipedia.org)
High1
- There is some evidence that flurothyl may actually possess general anesthetic properties at high concentrations that are masked by the more potent convulsant action. (wikipedia.org)
Effect1
- A molecular explanation for the difference between flurothyl and isoflurothyl was provided by electrophysiology studies that showed flurothyl was an antagonist (blocker) of neuronal GABAA receptors and had no effect on neuronal glycine receptors. (wikipedia.org)
Treatment2
- In some patients who had not responded to ECT, flurothyl treatment produced improvement. (wikipedia.org)
- The flurothyl treated patients showed less amnesia and confusion during the course of treatment with better patient acceptance. (wikipedia.org)
Seizure1
- METHODS: We evaluated multiple complex epileptic traits in a sampling of 35 CC inbred strains using the flurothyl-induced seizure and kindling paradigm. (nih.gov)
Form1
- An injectable form of flurothyl was formulated. (wikipedia.org)
Status1
- Flurothyl-induced status epilepticus was studied by light and electron microscopy (LM, EM) to determine the time course and structural features of neuronal necrosis in the vulnerable brain regions in epilepsy. (nih.gov)
Medicine1
- Flurothyl was at one time studied in psychiatric medicine for shock therapy, in a similar manner to other convulsant drugs such as pentetrazol, as an alternative to electroconvulsive therapy (ECT). (wikipedia.org)