Furosemide and Mannitol Suppression of Epileptic Activity in the Human Brain

Duke University, Durham, North Carolina, United States
Journal of Neurophysiology (Impact Factor: 2.89). 09/2005; 94(2):907-18. DOI: 10.1152/jn.00944.2004
Source: PubMed


Most research on basic mechanisms of epilepsy and the design of new antiepileptic drugs has focused on synaptic transmission or action potential generation. However, a number of laboratory studies have suggested that nonsynaptic mechanisms, such as modulation of electric field interactions via the extracellular space (ECS), might also contribute to neuronal hypersynchrony and epileptogenicity. To date, a role for nonsynaptic modulation of epileptic activity in the human brain has not been investigated. Here we studied the effects of molecules that modulate the volume and water content of the ECS on epileptic activity in patients suffering from neocortical and mesial temporal lobe epilepsy. Electrophysiological and optical imaging data were acquired from the exposed cortices of anesthetized patients undergoing surgical treatment for intractable epilepsy. Patients were given a single intravenous injection containing either 20 mg furosemide (a cation-chloride cotransporter antagonist) or 50 g mannitol (an osmolyte). Furosemide and mannitol both significantly suppressed spontaneous epileptic spikes and electrical stimulation-evoked epileptiform discharges in all subjects, completely blocking all epileptic activity in some patients without suppressing normal electroencephalographic activity. Optical imaging suggested that the spread of electrical stimulation-evoked activity over the cortex was significantly reduced by these treatments, but the magnitude of neuronal activation near the stimulating electrode was not diminished. These results suggest that nonsynaptic mechanisms play a critical role in modulating the epileptogenicity of the human brain. Furosemide and other drugs that modulate the ECS might possess clinically useful antiepileptic properties, while avoiding the side effects associated with the suppression of neuronal excitability.

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    • "The present study shows that furosemide blocks Cs þ -induced epileptiform activity in a concentration-dependent manner and thus adds to the list of in vitro and in vivo models which are sensitive to loop diuretics (Barbaro et al. 2004; Gutschmidt et al., 1998; Haglund and Hochman, 2005; Hochman et al., 1995; Holtkamp et al., 2003; Löscher et al., 2013; Margineanu and Klitgaard, 2006; Stringer and Pan, 1997). In earlier in vitro studies, effective anticonvulsant effects of furosemide were typically obtained with prolonged ( "
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    ABSTRACT: Though both in vivo and in vitro studies have demonstrated an anticonvulsant effect of the loop diuretic furosemide, the precise mechanism behind this effect is still debated. The current study investigates the effect of furosemide on Cs-induced epileptiform activity (Cs-FP) evoked in area CA1 of rat hippocampal slices in the presence of Cs(+) (5mM) and ionotropic glutamatergic and GABAergic receptor antagonists. As this model diverges in several respects from other epilepsy models it can offer new insight into the mechanism behind the anticonvulsive effect of furosemide. The present study shows that furosemide suppresses the Cs-FP in a dose-dependent manner with a near complete block at concentrations≥1.25mM. Because furosemide targets several types of ion transporters we examined the effect of more selective antagonists. Bumetanide (20μM), which selectively inhibits the Na-K-2Cl co-transporter (NKCC1), had no significant effect on the Cs-FP. VU0240551 (10μM), a selective antagonist of the K-Cl co-transporter (KCC2), reduced the ictal-like phase by 51.73±8.5% without affecting the interictal-like phase of the Cs-FP. DIDS (50μM), a nonselective antagonist of Cl(-)/HCO3(-)-exchangers, Na(+)-HCO3(-)-cotransporters, chloride channels and KCC2, suppressed the ictal-like phase by 60.8±8.1% without affecting the interictal-like phase. At 500μM, DIDS completely suppressed the Cs-FP. Based on these results we propose that the anticonvulsant action of furosemide in the Cs(+)-model is exerted through blockade of the neuronal KCC2 and Na(+)-independent Cl(-)/HCO3(-)-exchanger (AE3) leading to stabilization of the activity-induced intracellular acidification in CA1 pyramidal neurons. Copyright © 2015. Published by Elsevier B.V.
    No preview · Article · Aug 2015 · Brain research
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    • "Accumulating evidence indicates that furosemide possesses anticonvulsant properties (Haglund and Hochman, 2005; Hesdorffer et al., 2001; Holtkamp et al., 2003; Hochman et al., 1995), and it has been shown to suppress epileptic activity without affecting action potential generation or excitatory synaptic transmission (Ahmad et al., 1976; Hochman, 2012; Hochman and Schwartzkroin, 2000; Hochman et al., 1995; Traynelis and Dingledine, 1989). Furosemide was previously found to change the morphology of spontaneous spikes immediately prior to the suppression of interictal activity, and simultaneous intracellular recordings from pairs of pyramidal cells showed that these changes were correlated to the desynchronization of action potential firing times (Hochman and Schwartzkroin, 2000). "
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    ABSTRACT: The transgenic rat strain S284L-TG harbors the S284L mutant of the neuronal nicotinic acetylcholine receptor alpha4 subunit gene (CHRNA4), which is responsible for human autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE). S284L-TG rats have epileptic seizure phenotypes during slow-wave sleep, similar to those in NFLE. We previously demonstrated that γ-aminobutyric acid (GABA)ergic action of these rats was suppressed before the onset of ADNFLE seizures, and that glutamate release in the epileptic focus lesion was increased at the onset of epilepsy. Here, mRNA analysis revealed that Cl(-)-accumulating Na-K-2Cl cotransporter 1 (NKCC1) levels were increased and Cl(-)-extruding K-Cl cotransporter 1 and 2 (KCC1 and KCC2) levels were decreased at the onset of ADNFLE seizures in S284L-TG rat frontal cortexes, which perturbed the GABAergic inhibitory system. The reversal potentials (EGABA) of GABAA receptor-mediated currents in cortical layer V pyramidal neurons of S284L-TG rats also changed their polarity from hyperpolarization to depolarization, and S284L-TG miniature excitatory postsynaptic currents (mEPSCs), but not miniature inhibitory postsynaptic currents (mIPSCs), significantly increased in both amplitude and frequency. Administration of 25mg/kg/day furosemide before, but not after, the onset of interictal discharges prevented idiopathic epileptic activity, reversed the depolarizing shift of EGABA and increased mEPSC amplitude to normal levels. These data indicate that early treatment with an agent that normalizes pathogenesis has a prophylactic effect on epilepsy. We propose a strategy for prophylactic medication against idiopathic epilepsy through the suppression of epileptogenesis and/or ictogenesis.
    Full-text · Article · Sep 2013 · Epilepsy research
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    • "It has been observed for some time from studies both in vitro and in vivo that hyperosmolarity protects against seizures, whereas hypoosmolarity promotes generalized seizures (Andrew et al., 1989; Dudek et al., 1990; Haglund and Hochman, 2005; Maa et al., 2011; Traynelis and Dingledine, 1989). The consequences of cell swelling and reduction of the extracellular space (ECS) include increased extracellular resistance (Andrew et al., 1989; Dudek et al., 1990), magnified effect of local extracellular ion and transmitter accumulation (Nagelhus et al., 2004; Schwartzkroin et al., 1998), and enhanced neuronal synchrony and excitability (Andrew et al., 1989; Traynelis and Dingledine, 1989). "
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    ABSTRACT: It is estimated that one in 26 people will develop epilepsy in their lifetime, amounting to almost 12 million people in the United States alone (Hesdorffer et al., 2011). Epilepsy is a group of conditions characterized by sporadic occurrence of seizures and unconsciousness. This severely limits the ability to perform everyday tasks and leads to increased difficulty with learning and memory, maintenance of steady employment, driving, and overall socioeconomic integration. A greater understanding of the cellular and molecular mechanisms underlying seizures and epilepsy is necessary, as it may lead to novel antiepileptic treatments. In this chapter, we will review the current literature surrounding the involvement of glial cells in epilepsy with particular emphasis on review of human tissue studies and some possible underlying mechanisms. Based on the current evidence and hypotheses of glial mechanisms in epilepsy, novel therapeutic opportunities for the treatment of epilepsy will also be presented.
    Full-text · Article · Jan 2013 · Neurochemistry International
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