Neuropharmacology beyond reductionism - A likely prospect.

Neuropharmacology had several major past successes, but the last few decades did not witness any leap forward in the drug treatment of brain disorders. Moreover, current drugs used in neurology and psychiatry alleviate the symptoms, while hardly curing any cause of disease, basically because the etiology of most neuro-psychic syndromes is but poorly known. This review argues that this largely derives from the unbalanced prevalence in neuroscience of the analytic reductionist approach, focused on the cellular and molecular level, while the understanding of integrated brain activities remains flimsier.

Systems biology, complexity, and the impact on antiepileptic drug discovery.

The number of available anticonvulsant drugs increased in the period spanning over more than a century, amounting to the current panoply of nearly two dozen so-called antiepileptic drugs (AEDs). However, none of them actually prevents/reduces the post-brain insult development of epilepsy in man, and in no less than a third of patients with epilepsy, the seizures are not drug-controlled. Plausibly, the enduring limitation of AEDs' efficacy derives from the insufficient understanding of epileptic pathology.

Systems biology impact on antiepileptic drug discovery.

Systems biology (SB), a recent trend in bioscience research to consider the complex interactions in biological systems from a holistic perspective, sees the disease as a disturbed network of interactions, rather than alteration of single molecular component(s). SB-relying network pharmacology replaces the prevailing focus on specific drug-receptor interaction and the corollary of rational drug design of "magic bullets", by the search for multi-target drugs that would act on biological networks as "magic shotguns". Epilepsy being a multi-factorial, polygenic and dynamic pathology, SB approach appears particularly fit and promising for antiepileptic drug (AED) discovery.

Epileptic hypersynchrony revisited.

Synchronization of neuronal responses, which allows coordination of distributed activity patterns, is instrumental in brain functioning, as altered neuronal synchronization is involved in a variety of brain pathologies. Epileptic hypersynchrony chiefly relies on brain wiring, which, in a broader sense, means including astrocytic release of gliotransmitters and electrotonic coupling through gap junctions, beyond classical synaptic connections. Epileptic hypersynchrony also relies on electrical field effects and ion concentration changes in the extracellular space, and it relates to intracellular mechanisms underlying neuronal hyperexcitability.

Profile of the new pyrrolidone derivative seletracetam (ucb 44212) in animal models of epilepsy.

Seletracetam is a pyrrolidone derivative with a one-log-unit higher affinity for the synaptic vesicle protein 2A (SV2A) than levetiracetam (Keppra). This study explored its anticonvulsant properties in animal models of epilepsy. Seletracetam reduced both the amplitude and repetitive firing of population spikes induced by a high K(+)/low Ca(2+) concentration fluid (HKLCF) in rat hippocampal slices.

Brivaracetam inhibits spreading depression in rat neocortical slices in vitro.

Epilepsy and migraine are episodic neurological disorders with marked co-morbidity, making migraine common among epileptic patients. Conversely, several antiepileptic drugs (AEDs) are used as migraine-preventive medication. Cortical spreading depression (CSD) represents a transient suppression of bioelectric activity and is considered a key event in migraine and stroke.

Mechanisms of drug resistance in epilepsy: relevance for antiepileptic drug discovery.

Background: Epilepsy, the most common chronic neurological pathology, is symptomatically treated by present antiepileptic drugs (AEDs) in about two-thirds of the cases. Unfortunately, this proportion has not been significantly reduced despite the introduction of several new-generation AEDs.

Objective: This review challenges the utility of the paradigm of the excitation-inhibition imbalance for AED discovery and review mechanisms, presumed to be involved in drug-resistant epilepsy, with the purpose of discussing their relevance as targets for future AED discovery.

Effects of chronic treatment with levetiracetam on hippocampal field responses after pilocarpine-induced status epilepticus in rats.

Levetiracetam (Keppra) is a new generation antiepileptic drug characterized by a unique profile of activity in experimental models of epilepsy. It also has a distinct binding site in the brain, i.e.

The connexin 36 blockers quinine, quinidine and mefloquine inhibit cortical spreading depression in a rat neocortical slice model in vitro.

A protocol for inducing cortical spreading depression (SD) on rat neocortical slices in vitro, upon local application of calibrated approximately nl drops of KCl, 3M was used to elicit SD events, recorded at two different points on the slice. This in vitro model was validated by the inhibition of SD episodes by the NMDA antagonist MK-801 (20 microM), the reference SD blocker. Quinine, its stereoisomer quinidine, and mefloquine consistently inhibited the SD episodes.

Differential effects of cation-chloride co-transport-blocking diuretics in a rat hippocampal slice model of epilepsy.

The cation-Cl- co-transport-blocking loop diuretics have clinically known anticonvulsant activity, though they can also induce seizures. We explored the effects of ethacrynic acid (ETA), furosemide (FUR) and bumetanide (BUM), prototypical blockers of cation-Cl- co-transport, on the epileptiform field potentials induced in CA3 area of hippocampal slices from 5-weeks-old rats by a high K+-low Ca2+ perfusion fluid. That milieu induces frequent spontaneous field bursts, making single fimbrial stimuli to evoke several repetitive population spikes, of increased amplitude.

Caffeine-induced epileptiform field potentials in rat hippocampal slices: a pharmacological characterization.

Pharmacological modulation of the epileptiform electric activity induced by caffeine, 10 mM (CAF) on rat hippocampal slices was studied upon field potential recordings in CA3 area of the slices. This concentration of CAF, reportedly releasing Ca2+ ions from the endoplasmic reticulum, led single fimbrial stimuli to evoke repetitive population spikes (PSs) and induced periodic spontaneous field bursts. Carbamazepine, 50 microM reduced (by <40%) the number of repetitive PSs and the rate of spontaneous bursting, with no significant effect on the amplitude of evoked and spontaneous bursts.

Is the persistent sodium current a specific target of anti-absence drugs?

The persistent Na+ current (INaP) has been proposed as the putative target of the anti-absence antiepileptic drugs. Accordingly, the effect of reference anti-absence drugs ethosuximide (ESM) and valproate (VPA), and of the new antiepileptic drug levetiracetam (LEV), on INaP have been tested in CA1 hippocampal neurons and compared to the classic anticonvulsant phenytoin (PHT) and the neuroprotective agent riluzole (RIL). Whole-cell patch-clamp recordings of the slowly inactivating current, fully characterized as INaP, were performed with a standard voltage-step protocol on thin hippocampal slices prepared from rat brain.

Reduction of voltage-operated potassium currents by levetiracetam: a novel antiepileptic mechanism of action?

Levetiracetam (ucb L059; Keppra) is a novel antiepileptic drug. Its effects on action potential generation and voltage-operated potassium currents were studied in acutely isolated hippocampal CA1 neurones from rat and guinea pig, using the patch-clamp technique in the whole-cell configuration. (i) Levetiracetam reduced repetitive action potential generation and affected the single action potential.

Desynchronizing effect of levetiracetam on epileptiform responses in rat hippocampal slices.

The effect of levetiracetam on neuronal hypersynchrony and hyperexcitability was examined using simultaneous extra- and intracellular recordings in rat brain slices perfused with a high K+/low Ca2+ (HKLC) fluid. These findings were compared to results obtained with carbamazepine, valproate and clonazepam. The HKLC milieu induces in hippocampal CA3 area, spontaneous interictal bursts and epileptiform responses.

H3 agonist immepip markedly reduces cortical histamine release, but only weakly promotes sleep in the rat.

Presynaptic H3 receptors exert negative control on brain histamine synthesis and release and may thereby play a key role in the control of the sleep/wake cycle. This suggests that pharmacological stimulation by H3 receptor agonists may potentially decrease wakefulness and induce sleep. This study reports the effect of a potent and selective H3 agonist, immepip, on EEG assessed sleep/wake phases in Sprague-Dawley rats at doses that significantly modulate brain histamine release.

Levetiracetam has no significant gamma-aminobutyric acid-related effect on paired-pulse interaction in the dentate gyrus of rats.

Gamma-aminobutyric acid (GABA)ergic mechanisms of the novel antiepileptic drug, levetiracetam (Keppra), have been both favored and rejected. Since paired-pulse interaction is accepted in functionally assessing GABAergic mechanisms, we investigated whether levetiracetam affects the paired-pulse inhibition/facilitation of the field potentials, evoked in the dentate gyrus of urethane-anesthesized rats. This model revealed a strong paired-pulse inhibition at 20-ms interstimulus interval, a noteworthy paired-pulse facilitation at 80-ms interstimulus interval, and a moderate paired-pulse inhibition at 500-ms interstimulus interval.

Levetiracetam reduces caffeine-induced Ca2+ transients and epileptiform potentials in hippocampal neurons.

The effect of the novel antiepileptic drug levetiracetam on caffeine (10 mM)-induced intracellular calcium ([Ca2+]i) response was investigated in rat hippocampal neurons in culture, with the aim of exploring the cellular mechanisms of this new drug. Levetiracetam significantly reduced caffeine-induced [Ca2+]i) response, with maximum inhibition at 32 microM. The R-enantiomer of levetiracetam, ucb L060, which is devoid of anticonvulsant activity, at 32 microM had no effect on caffeine-induced [Ca2+]i) response.

Effect of the New Antiepileptic Drug Levetiracetam in an Animal Model of Mania.

The new antiepileptic drug levetiracetam (LEV, Keppra) was evaluated in a putative animal model for mania, namely, dexamphetamine-chlordiazepoxide mixture-induced hyperactivity in rats submitted to a Y-shaped maze test. Lithium chloride, sodium valproate, and carbamazepine, all clinically effective drugs in the treatment of acute mania, were used as comparators. The results indicate that the clinical references significantly attenuated the mixture-induced hyperactivity, thus confirming the sensitivity and pharmacological validity of this model.

Electrophysiological, neurochemical and regional effects of levetiracetam in the rat pilocarpine model of temporal lobe epilepsy.

This study compared levetiracetam (Keppra) with reference antiepileptic drugs (AEDs) in the rat pilocarpine model of temporal lobe epilepsy. Electroencephalogram (EEG) recordings showed that i.p.

Pilocarpine-induced epileptogenesis in the rat: impact of initial duration of status epilepticus on electrophysiological and neuropathological alterations.

This study characterized the electrophysiological and neuropathological changes in rat brains caused by pilocarpine (PILO)-induced status epilepticus (SE) of different duration. SE induced by PILO (375 mg/kg, i.p.