Schuchmann, S. et al. Experimental febrile seizures are precipitated by a hyperthermia-induced respiratory alkalosis. Nat. Med. 12, 817-823

Department of Biological and Environmental Sciences, University of Helsinki, Helsinki, Uusimaa, Finland
Nature Medicine (Impact Factor: 27.36). 08/2006; 12(7):817-23. DOI: 10.1038/nm1422
Source: PubMed


Febrile seizures are frequent during early childhood, and prolonged (complex) febrile seizures are associated with an increased susceptibility to temporal lobe epilepsy. The pathophysiological consequences of febrile seizures have been extensively studied in rat pups exposed to hyperthermia. The mechanisms that trigger these seizures are unknown, however. A rise in brain pH is known to enhance neuronal excitability. Here we show that hyperthermia causes respiratory alkalosis in the immature brain, with a threshold of 0.2-0.3 pH units for seizure induction. Suppressing alkalosis with 5% ambient CO2 abolished seizures within 20 s. CO2 also prevented two long-term effects of hyperthermic seizures in the hippocampus: the upregulation of the I(h) current and the upregulation of CB1 receptor expression. The effects of hyperthermia were closely mimicked by intraperitoneal injection of bicarbonate. Our work indicates a mechanism for triggering hyperthermic seizures and suggests new strategies in the research and therapy of fever-related epileptic syndromes.

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Available from: Ken Mackie, Oct 04, 2015
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    • "In neonatal seizures that have proven difficult to control using conventional antiepileptic drugs, a slight decrease in pH i has a pronounced suppressive effect on neuronal excitability (for review see, Löscher et al., 2013). Furthermore, carbon dioxide inhalation acts as a fast anticonvulsant on several seizure types which is likely attributable to the induction of a respiratory acidosis (Ohmori et al., 2013; Schuchmann et al., 2005; Tolner et al., 2011; Yang et al., 2014). The current study indicates that furosemide could be a usable alternative. "
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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.
    Brain research 08/2015; 1625. DOI:10.1016/j.brainres.2015.08.014 · 2.84 Impact Factor
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    • "Work in animal models suggests that it is the inflammatory process, in particular the neuroinflammation in the brain associated with a peripheral infection, that is one factor important in causing these seizures (for review Vezzani et al., 2011). A second probable factor is metabolic alkalosis caused by the elevated respiratory rate associated with the elevated temperature (Schuchmann et al., 2006). The vast majority of childhood febrile seizures do not lead to adult epilepsy (for review Patterson et al., 2014; Reid et al., 2009), yet experimental febrile seizures in rodents cause long term changes in brain excitability (Heida et al., 2005), alterations in expression of signaling molecules (Reid et al., 2013) and reorganization of neural circuitry (Reid et al., 2012). "
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    ABSTRACT: Fever has been recognized as an important symptom of disease since ancient times. For many years, fever was treated as a putative life-threatening phenomenon. More recently, it has been recognized as an important part of the body's defense mechanisms; indeed at times it has even been used as a therapeutic agent. The knowledge of the functional role of the central nervous system in the genesis of fever has greatly improved over the last decade. It is clear that the febrile process, which develops in the sick individual, is just one of many brain-controlled sickness symptoms. Not only will the sick individual appear "feverish" but they may also display a range of behavioral changes, such as anorexia, fatigue, loss of interest in usual activities, social withdrawal, listlessness or malaise, hyperalgesia, sleep disturbances and cognitive dysfunction, collectively termed "sickness behavior". In this review we consider the issue of whether fever and sickness behaviors are friend or foe during: a critical illness, the common cold or influenza, in pregnancy and in the newborn. Deciding whether these sickness responses are beneficial or harmful will very much shape our approach to the use of antipyretics during illness. Copyright © 2015. Published by Elsevier Inc.
    Brain Behavior and Immunity 07/2015; DOI:10.1016/j.bbi.2015.07.012 · 5.89 Impact Factor
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    • "These seizures are subtler than those evoked by chemoconvulsants but are nevertheless identifiable by sudden immobility, usually followed by facial automatism and tonic body flexion.32 Ictal electroencephalography (EEG) activity consists of spike-waves and trains of spikes with increased amplitude in the hippocampus, amygdala, and temporal cortex.82,83 Respiratory alkalosis also seems to be a component of hyperthermic seizures, as they can be mimicked by systemic bicarbonate. "
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    ABSTRACT: Abstract: Epilepsy is a chronic neurological condition characterized by recurrent seizures that affects millions of people worldwide. Comprehension of the complex mechanisms underlying epileptogenesis and seizure generation in temporal lobe epilepsy and other forms of epilepsy cannot be fully acquired in clinical studies with humans. As a result, the use of appropriate animal models is essential. Some of these models replicate the natural history of symptomatic focal epilepsy with an initial epileptogenic insult, which is followed by an apparent latent period and by a subsequent period of chronic spontaneous seizures. Seizures are a combination of electrical and behavioral events that are able to induce chemical, molecular, and anatomic alterations. In this review, we summarize the most frequently used models of chronic epilepsy and models of acute seizures induced by chemoconvulsants, traumatic brain injury, and electrical or sound stimuli. Genetic models of absence seizures and models of seizures and status epilepticus in the immature brain were also examined. Major uses and limitations were highlighted, and neuropathological, behavioral, and neurophysiological similarities and differences between the model and the human equivalent were considered. The quest for seizure mechanisms can provide insights into overall brain functions and consciousness, and animal models of epilepsy will continue to promote the progress of both epilepsy and neurophysiology research.
    Neuropsychiatric Disease and Treatment 09/2014; 10:1693-1705. DOI:10.2147/NDT.S50371 · 1.74 Impact Factor
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