A potential role for astrocytes in mediating the antiepileptic actions of furosemide in vitro.
Epileptic seizures are characterized by abnormal electrical discharge. In previous studies we established a powerful antiepileptic action for a commonly used diuretic (furosemide). However, it remains unclear precisely how furosemide terminates abnormal electrical discharges. To address this issue, we performed in vitro experiments to examine conditions where furosemide exerts antiepileptic activity and patch-clamp studies to analyze the effect of furosemide on neuronal membrane properties, synaptic function and inward potassium current. Furosemide was not found to alter synaptic field responses, excitatory postsynaptic currents or intrinsic membrane properties of principal hippocampal neurons. Our in vitro studies indicate that furosemide does not abolish spontaneous epileptiform bursting during co-application of Ba2+ or Cs+ ions (to block inwardly rectifying potassium channels). Our patch-clamp data indicate that furosemide enhances the function of astrocytic, but not neuronal, inward potassium channels and that this modulation may be required for its antiepileptic activity. Although a variety of antiepileptic drugs are already available, none of these compounds selectively target astrocytes while preserving synaptic/neuronal function. Thus, furosemide-mediated modulation of inward potassium current (on astrocytes) represents a new target for control of abnormal electrical discharge in the CNS.
Barbaro
N M
NM
Epilepsy Research Laboratory, Department of Neurological Surgery, University of California, 513 Parnassus Avenue, Box 0520, San Francisco, San Francisco, CA 94143, USA.
Takahashi
D K
DK
Baraban
S C
SC
D015761:4-Aminopyridine / Q000494:pharmacology; D000200:Action Potentials / Q000187:drug effects / Q000502:physiology; D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology*; D001253:Astrocytes / Q000187:drug effects* / Q000502:physiology; D001464:Barium / Q000494:pharmacology; D002586:Cesium / Q000494:pharmacology; D004827:Epilepsy / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects / Q000502:physiology; D005665:Furosemide / Q000494:pharmacology*; D006624:Hippocampus / Q000187:drug effects* / Q000502:physiology; D051379:Mice; D009434:Neural Pathways / Q000187:drug effects / Q000502:physiology; D009474:Neurons / Q000187:drug effects* / Q000502:physiology; D009924:Organ Culture Techniques; D018408:Patch-Clamp Techniques; D026902:Potassium Channel Blockers / Q000494:pharmacology; D015221:Potassium Channels / Q000187:drug effects / Q000502:physiology; D009435:Synaptic Transmission / Q000187:drug effects / Q000502:physiology
D000927:Anticonvulsants; D026902:Potassium Channel Blockers; D015221:Potassium Channels; D002586:Cesium; D001464:Barium; D005665:Furosemide; D015761:4-Aminopyridine