Differential effects of non-steroidal anti-inflammatory drugs on seizures produced by pilocarpine in rats

Ikonomidou-Turski, Chrysanthy; Cavalheiro, Ésper A.; Turski, Lechosław; Bortolotto, Zuner A.; Kleinrok, Z; Calderazzo‐Filho, Lineu S.; Turski, Waldemar A.

doi:10.1016/0006-8993(88)90556-2

Cited by 31 publications

(22 citation statements)

References 38 publications

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“…TLE is associated with changes in the expression of several inflammatory proteins and/or their receptors in distinct brain areas [22]. Studies have demonstrated that a series of non-steroidal anti-inflammatory drugs (NSAD) are anticonvulsant in pilocarpine-induced epileptic seizures [23]. Similarly, the NSAD dipyrone was also anticonvulsant in WARs [24].…”

Section: Discussionmentioning

confidence: 98%

Modulation of B1 and B2 kinin receptors expression levels in the hippocampus of rats after audiogenic kindling and with limbic recruitment, a model of temporal lobe epilepsy

Pereira

Gitaí

Paçó-Larson

et al. 2008

International Immunopharmacology

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Section: Discussionmentioning

confidence: 98%

Modulation of B1 and B2 kinin receptors expression levels in the hippocampus of rats after audiogenic kindling and with limbic recruitment, a model of temporal lobe epilepsy

Pereira

Gitaí

Paçó-Larson

et al. 2008

International Immunopharmacology

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“…The effects of these seizures on transporter expression were attenuated when the rats were pretreated with indomethacin. This nonselective COX-1/ COX-2 inhibitor was used in these in vivo experiments because it does not affect seizure severity in the pilocarpine model (Ikonomidou-Turski et al, 1988), whereas celecoxib has been reported to have both pro-and anticonvulsant effects in epilepsy models (Baik et al, 1999;Shafiq et al, 2003).…”

Section: Discussionmentioning

confidence: 99%

Seizure-Induced Up-Regulation of P-Glycoprotein at the Blood-Brain Barrier through Glutamate and Cyclooxygenase-2 Signaling

Bauer

Hartz²,

Pekcec³

et al. 2007

Mol Pharmacol

253

301

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Increased expression of drug efflux transporters at the bloodbrain barrier accompanies epileptic seizures and complicates therapy with antiepileptic drugs. This study is concerned with identifying mechanistic links that connect seizure activity to increased P-glycoprotein expression at the blood-brain barrier. In this regard, we tested the hypothesis that seizures increase brain extracellular glutamate, which signals through an N-methyl-D-aspartate (NMDA) receptor and cyclooxygenase-2 (COX-2) in brain capillaries to increase blood-brain barrier P-glycoprotein expression. Consistent with this hypothesis, exposing isolated rat or mouse brain capillaries to glutamate for 15 to 30 min increased P-glycoprotein expression and transport activity hours later. These increases were blocked by 5H-dibenzo[a,d]cyclohepten-5,10-imine (dizocilpine maleate) (MK-801), an NMDA receptor antagonist, and by celecoxib, a selective COX-2 inhibitor; no such glutamate-induced increases were seen in brain capillaries from COX-2-null mice. In rats, intracerebral microinjection of glutamate caused locally increased P-glycoprotein expression in brain capillaries. Moreover, using a pilocarpine status epilepticus rat model, we observed seizure-induced increases in capillary P-glycoprotein expression that were attenuated by administration of indomethacin, a COX inhibitor. Our findings suggest that brain uptake of some antiepileptic drugs can be enhanced through COX-2 inhibition. Moreover, they provide insight into one mechanism that underlies drug resistance in epilepsy and possibly other central nervous system disorders.Up to 40% of epileptic patients respond poorly if at all to conventional pharmacotherapy, and impaired drug uptake into the brain is considered to be one important contributor to therapeutic failure Kwan and Brodie, 2006). Seizures are known to increase the expression of drug efflux transporters at the blood-brain barrier, and recent experiments in animal models of epilepsy show that brain uptake of antiepileptic drugs can be significantly improved by coadministration of tariquidar, a selective and potent inhibitor of the ATP-driven drug efflux pump, P-glycoprotein (Brandt et al., 2006;van Vliet et al., 2006). Together, these findings point to increased P-glycoprotein expression as one consequence of seizure activity that limits pharmacotherapy with antiepileptic drugs.The present study is concerned with mechanistic links that connect seizure activity to increased P-glycoprotein expression. Our goals are to identify therapeutic targets that can be manipulated to prevent seizure-induced transporter overexpression and to improve pharmacotherapy with antiepileptic drugs. The combined in vitro/in vivo experiments are focused

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“…Consistent with this hypothesis, mefenamic acid concentrations are 40-80μM in plasma with therapeutic doses (Cryer & Feldman, 1998); fenamates can also cross the blood brain barrier (Houin et al, 1983;Bannwarth et al, 1989) and in overdose in humans are associated with coma and convulsions (Smolinske et al, 1990). In animal studies, mefenamic acid is anticonvulsant and neuroprotective against seizureinduced forebrain damage in rodents (Ikonomidou-Turski et al, 1988). The present study would suggest that the anticonvulsant effects of fenamates may be related, in part, to their efficacy to potentiate native GABA A receptors in the brain, although a recent study has suggested that activation of M-type K + channels may contribute to this action (Peretz et al, 2005) Finally, Joo and co-workers (2006) have recently reported that mefenamic acid provided neuroprotection against β-amyloid (Aβ 1-42 ) induced neurodegeneration and attenuated cognitive impairments in this animal model of Alzheimer's disease.…”

Section: Discussionmentioning

confidence: 99%

“…The fenamate NSAID, mefenamic acid (MFA) prevents convulsions and protects rats from seizure-induced forebrain damage evoked by pilocarpine (Ikonomidou-Turski et al, 1988) and is anti-epileptogenic against pentylenetetrazol (PTZ)-induced seizure activity, but at high doses induces seizures (Wallenstein, 1991). In humans, MFA overdose can lead to convulsions and coma (Balali-Mood et al, 1981;Young et al, 1979;Smolinske et al, 1990).…”

Section: Introductionmentioning

confidence: 99%

Characterization of the interaction between fenamates and hippocampal neuron GABAA receptors

Coyne

Patten

et al. 2007

Neurochemistry International

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Fenamate NSAIDs have several central effects, including anti-epileptic and neuroprotective actions. The underlying mechanism(s) of these actions are not presently understood. In this study, the effects of five members of the fenamate NSAID group were investigated on native ligand-gated ion channels expressed in cultured rat hippocampal neurons. All fenamates tested, (1-100μM) dose-dependently potentiated GABA-evoked currents; mefenamic acid (MFA) was the most potent and efficacious and was found to shift the GABA dose response curve to the left without effect on the maximum amplitude or the GABA Hill Slope. The modulation of GABA receptors by MFA was not reduced in the presence of the benzodiazepine antagonist, flumazenil (10μM) and was moderately voltagedependent. MFA at concentrations ≥10μM evoked dose-dependent currents in the absence of GABA. These currents were potentiated by diazepam (1μM) and blocked by bicuculline (10μM). The MFA (50μM) current-voltage relationship and reversal potential were similar to that evoked by GABA. MFA (1-100μM) had no effects on sub-maximal glycine, glutamate or NMDA evoked currents. These data show that fenamate NSAIDs are a highly effective class of GABA A receptor modulator and activators.

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Differential effects of non-steroidal anti-inflammatory drugs on seizures produced by pilocarpine in rats

Cited by 31 publications

References 38 publications

Modulation of B1 and B2 kinin receptors expression levels in the hippocampus of rats after audiogenic kindling and with limbic recruitment, a model of temporal lobe epilepsy

Modulation of B1 and B2 kinin receptors expression levels in the hippocampus of rats after audiogenic kindling and with limbic recruitment, a model of temporal lobe epilepsy

Seizure-Induced Up-Regulation of P-Glycoprotein at the Blood-Brain Barrier through Glutamate and Cyclooxygenase-2 Signaling

Characterization of the interaction between fenamates and hippocampal neuron GABAA receptors

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