Tobias Leniger

A new Chrna4 mutation with low penetrance in nocturnal frontal lobe epilepsy.

Summary:  Purpose: To identify and characterize the mutation(s) causing nocturnal frontal lobe epilepsy in a German extended family.

Seizure-associated headache in epilepsy.

Summary:  Purpose: Headache is often ignored as a symptom of epileptic seizures. The purpose of this prospective study was to analyze frequency, classification, and characteristics of seizure‐associated headache (SH) according to the criteria of the International Headache Society.

Carbonic anhydrase inhibitor sulthiame reduces intracellular pH and epileptiform activity of hippocampal CA3 neurons.

Summary:  Purpose: Sulthiame is a carbonic anhydrase (CA) inhibitor with an anticonvulsant effect in the treatment of benign and symptomatic focal epilepsy in children. The aim of the study was to elucidate the mode of action of sulthiame with respect to possible changes of intracellular pH (pHi) that might develop along with sulthiames anticonvulsant properties.

Clinical Characteristics of Patients With Comorbidity of Migraine and Epilepsy

Objective.—Neuronal hyperexcitability might explain the comorbidity of migraine and epilepsy. Spreading depression, a postulated pathophysiological mechanism of epileptic seizures and migraine with aura, may hypothetically be the link between the disorders in these comorbid conditions. The aim of the present study was to determine whether certain clinical characteristics associated with spreading depression are overrepresented in patients with comorbidity.

Topiramate modulates pH of hippocampal CA3 neurons by combined effects on carbonic anhydrase and Cl−/HCO3− exchange

Topiramate (TPM) is an anticonvulsant whose impact on firing activity and intracellular pH (pHi) regulation of CA3 neurons was investigated. Using the 4‐aminopyridine‐treated hippocampal slice model bathed in bicarbonate‐buffered solution, TPM (25–50 μM) reduced the frequency of epileptiform bursts and action potentials without affecting membrane potential or input resistance. Inhibitory effects of TPM were reversed by trimethylamine‐induced alkalinization. TPM also lowered the steady‐state pHi of BCECF‐AM‐loaded neuronal somata by 0.18±0.07 pH units in CO2/HCO3−‐buffered solution. Subsequent to an ammonium prepulse, TPM reduced the acidotic peak but clearly slowed pHi recovery. These complex changes were mimicked by the protein phosphatase inhibitor okadaic acid. Alkalosis upon withdrawal of extracellular Cl− was augmented by TPM. Furthermore, at decreased pHi due to the absence of extracellular Na+, TPM reversibly increased pHi. These findings demonstrate that TPM modulates Na+‐independent Cl−/HCO3− exchange. In the nominal absence of extracellular CO2/HCO3− buffer, both steady‐state pHi and firing of epileptiform bursts remained unchanged upon adding TPM. However, pHi recovery subsequent to an ammonium prepulse was slightly increased, as was the case in the presence of the carbonic anhydrase (CA) inhibitor acetazolamide. Thus, a slight reduction of intracellular buffer capacity by TPM may be due to an inhibitory effect on intracellular CA. Together, these findings show that TPM lowers neuronal pHi most likely due to a combined effect on Na+‐independent Cl−/HCO3− exchange and CA. The apparent decrease of steady‐state pHi may contribute to the anticonvulsive property of TPM.

Comparison of Intravenous Valproate With Intravenous Lysine‐Acetylsalicylic Acid in Acute Migraine Attacks

Objective.—The study compared efficacy and tolerability of intravenous valproate (iVPA) with intravenous lysine‐acetylsalicylic acid (iLAS) in acute migraine attacks.

Moclobemide reduces intracellular pH and neuronal activity of CA3 neurones in guinea-pig hippocampal slices—implication for its neuroprotective properties

Mechanisms underlying the neuroprotective properties of the weak MAO-A inhibitor moclobemide are not understood. Increasing evidence suggests that a moderate increase in intracellular free protons may contribute to neuroprotective properties due to a proton-mediated decrease in neuronal activity. Therefore, we studied effects of 10-700 microM moclobemide (i) on the intracellular pH (pH(i)) of BCECF-AM loaded CA3 neurones as well as (ii) on spontaneous action potentials and epileptiform activity (induced by bicuculline-methiodide, caffeine, or 4-aminopyridine) of CA3 neurones in the stratum pyramidale. Moclobemide-concentrations of > or = 300 microM reversibly reduced the steady-state pH(i) by up to 0. 25 pH-units within 5-20 min. Simultaneously, the frequency of spontaneous action potentials and epileptiform discharges became depressed. Moclobemide also abolished 4-aminopyridine-induced GABA-mediated hyperpolarisations suggesting that the inhibitory and acidifying effects of moclobemide do not result from an amplification of the GABA system. The stronger MAO-A inhibitors clorgyline or pargyline (both 10 microM) mimicked the moclobemide-effects. Investigating effects on pH(i)-regulation we found that 700 microM moclobemide impaired the recovery from intracellular acidification elicited by an ammonium prepulse which demonstrates an impairment of transmembrane acid extrusion. We suggest that the latter effect is responsible for the moderate decrease in the steady-state pH(i) which in turn reduced neuronal activity. This mechanism may substantially contribute to the neuroprotective properties of moclobemide.

Levetiracetam inhibits Na+-dependent Cl−/HCO3− exchange of adult hippocampal CA3 neurons from guinea-pigs

The novel anticonvulsant levetiracetam (LEV) was tested for effects on bioelectric activity and intracellular pH (pHi) regulation of hippocampal CA3 neurons from adult guinea‐pigs. In 4‐aminopyridine‐treated slices, LEV (10–100 μM) reduced the frequency of action potentials and epileptiform bursts of CA3 neurons by 30–55%, while the shape of these potentials remained largely unchanged. Suppressive effects were reversed by an increase of pHi with trimethylamine (TMA). Using BCECF‐AM‐loaded slices, we found that LEV (10–50 μM) reversibly lowered neuronal steady‐state pHi by 0.19±0.07 pH units in the presence of extracellular CO2/HCO3− buffer. In the nominal absence of extracellular CO2/HCO3− or in Na+‐free CO2/HCO3−‐buffered solution, LEV had no effect on steady‐state pHi. Recovery of pHi subsequent to ammonium prepulses remained unchanged in the absence of CO2/HCO3− buffer, but was significantly reduced by LEV in the presence of CO2/HCO3− buffer. These findings show that LEV inhibits HCO3−‐dependent acid extrusion, but has no effect on Na+/H+ exchange. LEV did not affect Na+‐independent Cl−/HCO3− exchange because intracellular alkalosis upon withdrawal of extracellular Cl− remained unchanged. These data show that LEV at clinically relevant concentrations inhibits Na+‐dependent Cl−/HCO3− exchange, lowers neuronal pHi, and thereby may contribute to its anticonvulsive activity.

Valproate acidifies hippocampal CA3-neurons—a novel mode of action

Various hypotheses try to explain the anticonvulsive and mood stabilizing effects of valproate. Among them, amplification of GABAergic inhibition and reduction of membrane excitability is favored. Here we show that superfusion with 0.1-1 mM valproate induced a moderate intracellular acidification of BCECF-AM-loaded CA3-neurons (hippocampal slices, guinea pig) which was measured as the difference between intracellular pH before (baseline pH(i)) and during valproate treatment (deltapH(i)). In two groups of neurons treated with 1 mM and 0.1-0.5 mM, deltapH(i) values amounted to 0.20 +/- 0.10 and 0.10 +/- 0.04 (deltapH(i) +/- S.D.), respectively, suggesting a dependence on the used valproate-concentration. DeltapH(i) did not correlate with the baseline pH(i). Furthermore, the acidification seems to be independent from an activation of postsynaptic GABA-A receptors, as it was not influenced by 0.1 mM picrotoxin. Since our previous studies clearly demonstrated a reduction of membrane excitability during moderate intracellular acidification, we suggest that the valproate-mediated intracellular acidification may substantially contribute to its anticonvulsive and mood stabilizing properties.