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 (12.5 micromol/L to 500 micromol/L) were applied. Membrane pressure was measured using a Wilhelmy film balance. In electrophysiological experiments, both drugs induced several effects in all studied neurons: membrane resistance increased, down-stroke of action potentials declined, and all types of chemical synaptic potentials decreased (the latter concerns pentylenetetrazol only). The threshold was 1 mmol/L of pentylenetetrazol and 12.5 micromol/L of etomidate. Epileptiform potentials developed in neurons that had expressed the membrane mechanisms underlying pacemaker potentials. The threshold of this development was again 1 mmol/L of pentylenetetrazol and 12.5 micromol/L of etomidate. Epileptiform depolarizations appeared with 40 mmol/L of pentylenetetrazol and 500 micromol/L of etomidate. In biochemical experiments, both drugs incorporated into an artificial phospholipids membrane and increased pressure in the membrane. The threshold of pressure increase was 1 mmol/L of pentylenetetrazol and 12.5 micromol/L of etomidate. Pressure increased dose-dependently and was 69% and 63% above starting pressure of 10 mN/m with epileptogenic concentrations of pentylenetetrazol (40 mmol/L) and of etomidate (500 micromol/L), respectively. It is postulated that amphiphilic substances incorporate into cell membranes and increase intramembranous pressure, and that this disturbs several membrane processes mechanically and leads to epileptic depolarizations in pacemaker neurons.
Altrup
Ulrich
U
Institute of Experimental Epilepsy Research, University of Münster, Hüfferstr. 68, 48149 Münster, Germany. altrup@uni-muenster.de
Häder
Marc
M
Cáceres
José Luis Hernández
JL
Malcharek
Stefan
S
Meyer
Michaela
M
Galla
Hans-Joachim
HJ
D000200:Action Potentials / Q000187:drug effects / Q000502:physiology; D000818:Animals; D003292:Convulsants / Q000378:metabolism*; D004195:Disease Models, Animal; D004558:Electric Stimulation; D004827:Epilepsy / Q000139:chemically induced / Q000378:metabolism*; D005045:Etomidate / Q000378:metabolism*; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects / Q000502:physiology; D017952:Ganglia, Invertebrate / Q000166:cytology / Q000187:drug effects; D006372:Helix, Snails; D066298:In Vitro Techniques; D053444:Inhibitory Postsynaptic Potentials / Q000187:drug effects / Q000502:physiology; D008563:Membrane Lipids / Q000378:metabolism*; D008564:Membrane Potentials / Q000187:drug effects* / Q000502:physiology; D008959:Models, Neurological; D009474:Neurons / Q000187:drug effects* / Q000502:physiology; D018408:Patch-Clamp Techniques; D010433:Pentylenetetrazole / Q000378:metabolism*; D010743:Phospholipids / Q000378:metabolism
D003292:Convulsants; D008563:Membrane Lipids; D010743:Phospholipids; D010433:Pentylenetetrazole; D005045:Etomidate