Abstracts

Neuronal hyperexcitability has been a major focus in research on basic mechanisms of epilepsy and in the design of antiepileptic medications. Previous [italic]in vitro [/italic]studies suggested that furosemide (Lasix), a commonly used diuretic, could block [lsquo]hypersynchronized[rsquo] epileptiform activity [italic]without[/italic] suppressing neuronal excitability. It has been suggested that furosemide mediates its antiepileptic effects through nonsynaptic mechanisms, possibly involving changes in the size of the extracellular space (ECS). Here we study the effects of furosemide and mannitol (an osmolyte that is also known to modulate the ECS) in human patients with medically intractable epilepsy. Intraoperative studies were performed on 13 patients with medically intractable epilepsy, who had given informed consent and adhered to a protocol that was approved by the Duke Human Subject Committee (IRB Protocol #2082). The age of the patients varied from 12 to 56 years old, with 3 male/ 11 female. All experiments were performed intraoperatively on patients during their surgical procedure for the treatment of intractable epilepsy. After the cortex was exposed, optical imaging was performed while electrophysiological recordings were acquired from an array of EEG electrodes placed directly on the cortical surface. Patients were given intravenous injections of either furosemide (20 mg) or mannitol (50 g). The effects of these treatments were studied on spontaneous interictal spiking and electrical stimulation-evoked afterdischarge activity. Intravenously injected furosemide significantly suppressed spontaneous interictal epileptic spikes and electrical stimulation-evoked epileptiform activity in all patients tested. Neither the response of the cortex to electrical stimulation as measured with optical imaging, nor EEG activity recorded from non-epileptic cortex, was suppressed by furosemide, suggesting the furosemide did not suppress cortical excitability. Mannitol, an osmolyte, similarly suppressed epileptic activity. These studies indicate that i) furosemide suppresses epileptic activity, and ii) nonsynaptic mechanisms may play a significant role in the maintenance of epileptic activity in the human brain. These results suggest novel nonsynaptic pharmacological targets for the development of new antiepileptic medications. Molecules that modulate the extracellular space, either directly or through antagonism of the cation-chloride cotransport system, might provide a potent means to control seizure activity while avoiding the side effects associated with current therapies that suppress neuronal excitability (Supported by Junior Investigator Research Grant Award from the Epilepsy Foundation of America, and NIH/NINDS R21NS042341 (DWH); NIH/NINDS K08NS01828 (MMH).)