Epileptogenic drugs in a model nervous system: electrophysiological effects and incorporation into a phospholipid layer.

Mechanisms of epileptiform activity in a model nervous system (buccal ganglia of Helix pomatia) are presented. The ganglia contain the identified giant neurons B1 through B4. For epileptiform activity, pentylenetetrazol (1 mmol/L to 40 mmol/L) or etomidate (12.

Block of spontaneous termination of paroxysmal depolarizations by forskolin (buccal ganglia, Helix pomatia).

Effects of cAMP-activated protein kinases (PKA) on epileptic activity are at present studied in a model nervous system. Identified neurons in the buccal ganglia of the snail Helix pomatia were recorded with intracellular microelectrodes in a continuously perfused experimental chamber. Epileptiform activity appeared regularly in neuron B3 when the saline contained pentylenetetrazol (20-40 mM).

Continuous increase of epileptogenic effects following application of proteolytic enzymes (buccal ganglia of Helix pomatia).

Epileptic activity of neurons consists of paroxysmal depolarization shifts (PDS) which can be induced presumably in any nervous system by application of an epileptogenic drug. The spontaneous appearance of epileptic activity, however, is based on a largely unknown process which increases susceptibility to epileptic activity (seizure susceptibility in man). It is presently shown that the treatment of ganglia with proteolytic enzymes (Pronase) decreases the effective concentration of epileptogenic drugs, i.

Pacemaker potentials are the physiologic basis of epileptiform activity in the buccal ganglia of Helix pomatia.

Mechanisms of epileptic activity in nervous systems were studied using the identified neurons B1 through B4 in the buccal ganglia of the snail Helix pomatia as a model system. Activities were recorded with intracellular microelectrodes. Epileptiform activity was induced by bath application of an epileptogenic drug (pentylenetetrazol: 1 mM to 40 mM, or etomidate: 0.

Epileptogenicity and epileptic activity: mechanisms in an invertebrate model nervous system.

Epileptic seizures are based on paroxysmal depolarization shifts (PDS) which are synchronized in many neurons. Mechanisms underlying PDS and seizures are still not understood. The present review is based on studies using the buccal ganglia of the snail Helix pomatia as a model nervous system.

Endogenous pacemaker potentials develop into paroxysmal depolarization shifts (PDSs) with application of an epileptogenic drug.

Well-known invertebrate ganglia (buccal ganglia of Helix pomatia, abdominal ganglia of Aplysia californica) were used to study the contribution of synaptic potentials, central pattern generators, and endogenously generated neuronal potentials to the development of epileptiform activity. Epileptiform activity which was induced with application of pentylenetetrazol (1 to 100 mM) or etomidate (0.12 to 1.

Paroxysmal depolarization shifts (PDS) induce non-synaptic responses in neighboured neurons (buccal ganglia, Helix pomatia).

A non-synaptic spread of excitation between neighboured neurons was studied in a model nervous system using epileptiform activity. The identified giant neuron B3 in the buccal ganglia of Helix pomatia reliably generated paroxysmal depolarization shifts (PDS) when treated with pentylenetetrazol or etomidate. Simultaneous recordings of neuron B3 and other neurons showed that each PDS in neuron B3 was accompanied by a depolarization in the other neurons.

Effects of valproate derivatives II. Antiepileptic efficacy in relation to chemical structures of valproate sugar esters.

The structure effect relationships of derivatives of the antiepileptically active ester of valproate (VPA) 3,4:5,6-Di-O-isopropylidene-1-O-(2-propylpentanoyl)-D-mannitol (1) have been studied using intracellular recording to record the membrane potential of single neurons (buccal ganglia, Helix pomatia). Epileptiform activity was induced by the epileptogenic drug pentylenetetrazol. The effects of several derivatives on epileptiform activity were compared with those of the relay compound 1.

Effects of valproate derivatives I. Antiepileptic efficacy of amides, structural analogs and esters.

Derivatives of the antiepileptic drug valproate (VPA, 2-propylpentanoic acid) have been synthesized and tested in order to improve the intracellular availability of VPA. The buccal ganglia of Helix pomatia were used as a test nervous system and antiepileptic efficacies were reconfirmed using rat cortex in vivo. Epileptiform activities consisted of typical paroxysmal depolarization shifts (PDS) which appeared in the identified neuron B3 with application of pentylenetetrazol.

Heptanol exerts epileptiform effects in identified neurons of the buccal ganglia of Helix pomatia.

1-Heptanol (0.2-5.0 mM) known to block electrical contacts was tested under epileptic and non-epileptic conditions in the buccal ganglia of Helix pomatia.

Epileptic neurons induce augmenting synaptic depolarizations in non-epileptic neurons (buccal ganglia, Helix pomatia).

Spread of epileptic activity was studied by inducing epileptiform activity (pentylenetetrazol, PTZ) in one part of a nervous system and by analyzing responses of neurons in a non-PTZ-treated part (identified neurons, paired buccal ganglia, Helix pomatia). Paroxysmal depolarization shifts (PDS) induced time-locked depolarizations in non-epileptic neurons (latency ca. 5 s, duration ca.

Prediction of neurotoxic potency of hazardous substances with a modular in vitro test battery.

Neurotoxic action was investigated on different model nervous systems linked to a modular in vitro test battery. Voltage operated potassium channels and glutamate operated ion channels expressed in oocytes of the clawed frog Xenopus laevis by injection of cRNA (cloned RNA) or mRNA, respectively, as well as isolated neurons and isolated neuronal networks from the buccal ganglia of the snail Helix pomatia, were used as consecutive modules of different complexity. Lead (Pb2+) was chosen as a known neurotoxic model substance to evaluate the suitability of the test battery to predict the neurotoxic potency of hazardous substances, to establish dose-response relationships, and to investigate the basic mechanisms involved in neurotoxicity.

A method to study the effects of an epileptic focus on non-epileptic nervous tissue.

Locally applied epileptogenic drugs directly affect the local cells which project their epileptic activity into the surrounding tissue. This paper describes an experimental set-up which allows differentiation of direct effects of an epileptogenic drug from indirect ones, which are synaptically projected. The set-up consisted of an experimental chamber which enabled the isolated superfusion of a part of a nervous system with a drug.

Alterations of neuronal fibers after epileptic activity induced by pentylenetetrazole: fine structure investigated by calcium cytochemistry and neurobiotin labeling (buccal ganglia, Helix pomatia).

The influence of epileptic activity on both the fine structure of neuronal processes and the subcellular distribution of calcium-binding sites was investigated in an epileptic model system, the buccal ganglion of Helix pomatia. Pentylenetetrazole was used to induce epileptic activity. Calcium-binding sites were visualized as electron-dense precipitates.

Simultaneous blockade of intracellular calcium increases and of neuronal epileptiform depolarizations by verapamil.

The specific L-type calcium channel blocker verapamil exerts an antiepileptic effect on neurons. This effect is assumed to depend on the blockade of transmembraneous calcium flux during epileptic discharges. In order to test this hypothesis, fura-dextran loaded snail neurons were rendered epileptic by pentylenetetrazole (40 mmol/l).

Epileptic discharges induced by pentylenetetrazol: ultrastructural alterations in identified neurons and glial cells (Helix pomatia).

The effects of sustained epileptic activity induced by pentylenetetrazol on morphology of buccal ganglia of Helix pomatia were investigated. Neuronal somata and processes as well as glial cells were evaluated after 5 hours of epileptic activity and after 5 hours under control conditions. After epileptic activity neurons showed signs of degeneration consisting of condensation of nuclear chromatin, decreased activity of Golgi apparatus, increased numbers of lamellar bodies and multivesicular bodies, clusters of vesicles and vacuoles, loss of microtubuli, and scattered lamellar bodies.

Attenuation of a voltage-dependent sodium current by GABA (identified neurons, buccal ganglia, Helix pomatia).

The action of systemically applied GABA on voltage-dependent currents of the identified neurons B1-B4 in the buccal ganglia of Helix pomatia were investigated by conventional voltage clamp techniques. In the B4 neuron, superfusion with sodium-free solution or addition of tetrodotoxin to the bath medium abolished the voltage dependent inward current. This voltage dependent sodium current was reduced with GABA application.

Simultaneous and continuous measurement of free concentration of valproate in blood and extracellular space of rat cerebral cortex.

Free concentration of valproate (VPA) was measured simultaneously and continuously in blood and in the extracellular space of cerebral cortex of rats by VPA-selective microelectrodes. Constant amounts of VPA were injected into the femoral vein with differing duration of injection. Immediately after drug application, the concentration of free VPA in blood and brain increased to a peak value, the degree of which increased with the speed of injection.

Identified neuronal individuals in the buccal ganglia of Helix pomatia.

The buccal ganglia of Helix pomatia are used as model nervous structures in neurophysiological and epileptological studies. Many basic problems concerning membrane physics and the functioning of single neurons and neuronal networks can be easily studied using these ganglia. The model character derives mainly from the relative simplicity of this nervous system and the fact that it contains large, visually identifiable neurons.

Diffusion analysis of valproate and trans-2-en-valproate in agar and in cerebral cortex of the rat.

The diffusion of valproate (VPA) and trans-2-en-valproate were studied in agar gel and in the cerebral cortex of the rat using pressure microejection and VPA-selective microelectrodes. From the agar measurements a free diffusion coefficient for VPA of 6.52 x 10(-6) cm2.

Effects of valproate on early and late potassium currents of single neurons.

The effects of valproate sodium (VPA) on potassium currents were tested in identified neurons of the snail Helix pomatia. VPA was extracellularly and intracellularly applied. VPA (i) had no effects on the current-voltage relation of the early potassium outward current (IA), (ii) shifted the steady state inactivation function of IA to more positive potentials, (iii) increased the amplitude of the late potassium outward currents.

Identified neuronal individuals in the buccal ganglia of Helix pomatia.

The buccal ganglia of Helix pomatia are used as model nervous structures in neurophysiological and in epileptological studies. Many basic problems concerning membrane physics, functioning of the single neurons and of neuronal networks can be studied easily using these ganglia. The model character mainly comes from the relative simplicity of this nervous system and that it contains large visually identifiable neurons.

Effects of valproate in a model nervous system (buccal ganglia of Helix pomatia): II. Epileptogenic actions.

High concentrations of valproate (VPA; greater than 20 mM) depolarized identified neuronal individuals in the buccal ganglia of Helix pomatia and transiently induced paroxysmal depolarization shifts (PDS). Threshold concentration of VPA for the induction of PDS was decreased (a) by increased seizure susceptibility, (b) by increased concentrations of derivatives of VPA, and (c) by increased H+ concentrations. Intrasomatic injection of VPA did not induce PDS.

Effects of valproate in a model nervous system (buccal ganglia of Helix pomatia): I. Antiepileptic actions.

Cellular actions of valproate (VPA) were studied using intracellular recordings of identified neuronal individuals in the buccal ganglia of Helix pomatia. Under nonepileptic conditions, VPA induced (a) a hyperpolarization, (b) slight changes in action potentials (AP), and (c) an increase in membrane resistance. Under epileptic conditions (i.