Preclinical assessment of proconvulsant drug activity and its relevance for predicting adverse events in humans. Eur J Pharmacol

Department of Pharmacology, Toxicology, and Pharmacy, University of Veterinary Medicine Hannover, Hannover, Germany.
European journal of pharmacology (Impact Factor: 2.53). 04/2009; 610(1-3):1-11. DOI: 10.1016/j.ejphar.2009.03.025
Source: PubMed


Safety pharmacology studies, which are performed before first studies with investigational drugs in humans, often include experiments on proconvulsant drug activity, because such drugs are thought to promote seizures by decreasing seizure threshold. A commonly used model for the assessment of proconvulsant activity of investigational or marketed drugs is the timed intravenous pentylenetetrazole (PTZ) infusion seizure test, in which the latency to myoclonic or clonic seizures is determined by PTZ infusion in mice or rats. This test provides an extremely sensitive parametric method for assessing seizure threshold and allows detecting both anticonvulsant and proconvulsant drug effects. The aim of this review is to critically review the concept of "proconvulsant" drug activity and discuss data obtained by the PTZ and other seizure threshold tests as well as the various factors that may affect seizure threshold determinations. Furthermore, preclinical and clinical data on proconvulsant drug activity are compared. It is concluded that a battery of different tests is needed to provide the most reliable conclusions about the proconvulsant profile, if any, of drugs. Furthermore, misconceptions regarding proconvulsant drug effects, which can result in the undertreatment of brain diseases, are discussed.

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    • "For this purpose, rats were closely observed until they resumed normal behavior, which typically was about 1—2 h after PTZ infusion. The intravenous PTZ test can be repeatedly performed in the same rat at intervals of about 48 h, allowing the study of changes in threshold over time (Löscher, 2009). To prevent a kindling effect, in the present study the number of PTZ seizure threshold determinations was limited to a maximum of five in each rat, with intervals of at least one week between testing. "
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    ABSTRACT: Neuronal transplantation is a promising experimental treatment approach for intractable epilepsies, but rejection of porcine or human cells in rodent epilepsy models requires adequate immunosuppression to enable long-term survival of xenografts. The commonly used immunosuppressive drug cyclosporine A (CsA) itself was suggested to affect seizure thresholds. However, putative pro- or anticonvulsant effects of CsA have not yet been sufficiently explored in a direct comparison study involving different preparations, dosages, and application routes. We therefore comprehensively investigated the effects of acute versus chronic treatment using different dosages (5mg/kg, 10mg/kg), application routes (i.p., s.c.), and preparations of CsA (pure substance solved in polyethoxylated castor oil and a ready-to-use drug additionally containing ethanol) on acute seizure thresholds in rats in the pentylenetetrazole seizure threshold test and verified the most harmless protocol in the chronic amygdala-kindling model for temporal lobe epilepsy. None of the CsA treatment regimens induced acute changes of seizure thresholds. Chronic CsA treatment also did not robustly change seizure thresholds. As evaluated by whole blood analyses, bioavailability of CsA was significantly higher after i.p. application of the ready-to-use preparation compared to the pure substance and compared to s.c. Observed adverse effects differed between CsA treatment regimens and included reversible diarrhea, lowered body temperature, and tremor, the latter two of which were also induced by vehicle injections containing ethanol and/or polyethoxylated castor oil. Our data suggest that chronic treatment (2 weeks) with 10mg/kg CsA injected i.p. in the ready-to-use preparation is an appropriate protocol for use in neural transplantation in epilepsy research applying the presently used rat models. Transplantation studies in experimental epilepsy research require a careful assessment of putative CsA effects on seizure thresholds in the specific experimental settings to be used. Copyright © 2015 Elsevier B.V. All rights reserved.
    Epilepsy research 05/2015; 112. DOI:10.1016/j.eplepsyres.2015.02.006 · 2.02 Impact Factor
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    • "For anticonvulsant activity evaluation, the i.v. PTZ timed infusion test and the 6-Hz psychomotor model of partial epilepsy were selected due to their unique sensitivity for identification of AEDs with a wide range of mechanisms of action [29] [30] [31] [32] [33] [44] [57] including detection of the anticonvulsant properties of levetiracetam that were “overlooked” by MES and s.c. PTZ tests [30] [33] [58]. "
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    ABSTRACT: In a previous study, we uncovered the anticonvulsant properties of turmeric oil and its sesquiterpenoids (ar-turmerone, α-, β-turmerone and α-atlantone) in both zebrafish and mouse models of chemically-induced seizures using pentylenetetrazole (PTZ). In this follow-up study, we aimed at evaluating the anticonvulsant activity of ar-turmerone further. A more in-depth anticonvulsant evaluation of ar-turmerone was therefore carried out in the i.v. PTZ and 6-Hz mouse models. The potential toxic effects of ar-turmerone were evaluated using the beam walking test to assess mouse motor function and balance. In addition, determination of the concentration-time profile of ar-turmerone was carried out for a more extended evaluation of its bioavailability in the mouse brain. Ar-turmerone displayed anticonvulsant properties in both acute seizure models in mice and modulated the expression patterns of two seizure-related genes (c-fos and brain-derived neurotrophic factor [bdnf]) in zebrafish. Importantly, no effects on motor function and balance were observed in mice after treatment with ar-turmerone even after administering a dose 500-fold higher than the effective dose in the 6-Hz model. In addition, quantification of its concentration in mouse brains revealed rapid absorption after i.p. administration, capacity to cross the BBB and long-term brain residence. Hence, our results provide additional information on the anticonvulsant properties of ar-turmerone and support further evaluation towards elucidating its mechanism of action, bioavailability, toxicity and potential clinical application.
    PLoS ONE 12/2013; 8(12):e81634. DOI:10.1371/journal.pone.0081634 · 3.23 Impact Factor
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    • "The mechanism involved in the dual effect of citalopram on seizure susceptibility is not yet fully understood. In a recent review by Loscher, the apparent dose-dependent effect of antidepressants on seizure threshold was documented: low but clinically relevant doses of antidepressants appear to exert an anticonvulsant effect in a variety of animal seizure models via an increase in noradrenaline or 5-HT synaptic levels, while proconvulsant activity may be seen at supra-therapeutic doses (Loscher, 2009). "
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    ABSTRACT: Citalopram is a selective serotonin reuptake inhibitor (SSRI), widely used in the treatment of depressive disorders. It has been shown that citalopram affects seizure susceptibility. Although the exact mechanism of these effects are not yet fully understood, recent data suggest that 5HT(3) receptors and nitric oxide (NO) might participate in the central effects of SSRIs. In this study in a mouse model of clonic seizure induced by pentylenetetrazole we investigated whether 5-HT(3) receptors are involved in the effects of citalopram on seizure threshold. In our experiments, citalopram at lower doses (0.5 and 1mg/kg, i.p) significantly increased the seizure threshold and at higher doses (≥25mg/kg) showed proconvulsive effects. Moreover, mCPBG (a 5-HT(3) receptor agonist) at low and non-effective doses augmented while non-effective doses of tropisetron prevented the anticonvulsive properties of citalopram. On the other hand, Low doses of nitric oxide synthase inhibitors l-NAME and 7-NI alone or in combination with lower doses of 5-HT(3) receptor agonist enhanced the anticonvulsive property of citalopram, while l-arginine (NO precursor) alone or in combination with tropisetron blocked the protective effect of citalopram. In summary, our findings demonstrate that 5-HT(3) receptor mediates the anticonvulsant properties of low doses of citalopram, whereas it seems that the proconvulsive effect is mostly mediated through the NO pathway and can be totally blocked by NOS inhibitors. This could propose a new approach toward finding the mechanism of citalopram activity, curtailing the adverse effects of citalopram and perhaps managing the convulsions as a vicious consequence of citalopram overdose.
    Epilepsy research 05/2012; 101(3):217-27. DOI:10.1016/j.eplepsyres.2012.04.004 · 2.02 Impact Factor
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