Temporal patterns of the cerebral inflammatory response in the rat lithium–pilocarpine model of temporal lobe epilepsy

Voutsinos-Porche, Brigitte; Koning, Estelle; Kaplan, Hervé; Ferrandon, Arielle; Guenounou, Moncef; Nehlig, Astrid; Motté, Jacques

doi:10.1016/j.nbd.2004.07.023

Cited by 130 publications

(81 citation statements)

References 85 publications

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“…In the epileptic brain, activation of NMDA receptors and subsequent downstream events contribute to excitotoxic damage and loss of neurons (Gardoni and Di Luca, 2006). Transcriptional activation of the gene encoding COX-2 has also been reported in a number of epilepsy models (Voutsinos-Porche et al, 2004;Kawaguchi et al, 2005;Takemiya et al, 2006;Lee et al, 2007) and in the human epileptic brain (Desjardins et Fig. 6.…”

Section: Discussionmentioning

confidence: 94%

“…First, glutamate released from neurons during an epileptic seizure accumulates in brain interstitial fluid (Holmes, 2002), and glutamate has been shown to increase P-glycoprotein expression in rat brain endothelial cells (Zhu and Liu, 2004). Second, enhanced glutamatergic signaling increases COX-2 (Strauss and Marini, 2002), which reaches its highest expression levels in the early phase after an epileptic seizure (Voutsinos-Porche et al, 2004;Lee et al, 2007). Third, in rat renal mesangial cells, COX-2 proved to be a potent inducer of P-glycoprotein (Patel et al, 2002).…”

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confidence: 99%

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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

246

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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Section: Discussionmentioning

confidence: 94%

mentioning

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

246

301

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“…In the cytotoxic edema, the glutamate hyperstimulation causes intracellular Ca 2+ increase and promotes cytotoxicity in neurons and glial cells [64,70]. Conversely, in the vasogenic edema, the cellular signaling triggered by SE can induce proinflammatory cytokines release and increases the production of kinins [71][72][73][74][75][76][77][78]. The kinins along with the cytokines may affect the junction of blood vessel epithelial cells and reduce the integrity of the tight junctions in endothelial cells walls, leading to a dysfunction of the blood brain barrier and consequently increasing the vascular permeability and accumulation of extracellular fluid [63,70,79,80].…”

Section: Discussionmentioning

confidence: 99%

Silencing of P2X7R by RNA interference in the hippocampus can attenuate morphological and behavioral impact of pilocarpine-induced epilepsy

Amorim

Araújo

Valero

et al. 2017

Purinergic Signalling

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Cell signaling mediated by P2X7 receptors (P2X7R) has been suggested to be involved in epileptogenesis, via modulation of intracellular calcium levels, excitotoxicity, activation of inflammatory cascades, and cell death, among other mechanisms. These processes have been described to be involved in pilocarpine-induced status epilepticus (SE) and contribute to hyperexcitability, resulting in spontaneous and recurrent seizures. Here, we aimed to investigate the role of P2X7R in epileptogenesis in vivo using RNA interference (RNAi) to inhibit the expression of this receptor. Small interfering RNA (siRNA) targeting P2X7R mRNA was injected into the lateral ventricles (icv) 6 h after SE. Four groups were studied: SalineVehicle, Saline-siRNA, Pilo-Vehicle, and Pilo-siRNA. P2X7R was quantified by western blotting and neuronal death assessed by Fluoro-Jade B histochemistry. The hippocampal volume (edema) was determined 48 h following RNAi. Behavioral parameters as latency to the appearance of spontaneous seizures and the number of seizures were determined until 60 days after the SE onset. The Saline-siRNA and Pilo-siRNA groups showed a 43 and 37% reduction, respectively, in P2X7R protein levels compared to respective vehicle groups. Neuroprotection was observed in CA1 and CA3 of the PilosiRNA group compared to Pilo-Vehicle. P2X7R silencing in pilocarpine group reversed the increase in the edema detected in the hilus, suprapyramidal dentate gyrus, CA1, and CA3; reduced mortality rate following SE; increased the time to onset of spontaneous seizure; and reduced the number of seizures, when compared to the Pilo-Vehicle group. Therefore, our data highlights the potential of P2X7R as a therapeutic target for the adjunct treatment of epilepsy.

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“…Marchi et al (2009) reported that lithium induces systemic inflammatory events and blood-brain barrier damage in rats before administration of pilocarpine and that blood-brain barrier damage and SE onset could be reduced by pretreatment with an interleukin (IL)-1␤ antagonist. Pilocarpine and SE itself are also known to induce neuroinflammatory responses (Voutsinos-Porche et al, 2004;Vezzani and Granata, 2005;Marchi et al, 2007), but the adaptive immune response to lithium clearly differentiates the lithium-pilocarpine model from all other SE models. However, with respect to the effects of inflammation on SE, it is also important to note that administration of the proinflammatory bacterial endotoxin lipopolysaccharide 72 h before pilocarpine did not potentiate its convulsant activity (Dmowska et al, 2010).…”

Section: Antiepileptogenesis After Brain Insultsmentioning

confidence: 99%

Prevention or Modification of Epileptogenesis after Brain Insults: Experimental Approaches and Translational Research

Löscher¹,

Brandt²

2010

Pharmacol Rev

350

366

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Temporal patterns of the cerebral inflammatory response in the rat lithium–pilocarpine model of temporal lobe epilepsy

Cited by 130 publications

References 85 publications

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

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

Silencing of P2X7R by RNA interference in the hippocampus can attenuate morphological and behavioral impact of pilocarpine-induced epilepsy

Prevention or Modification of Epileptogenesis after Brain Insults: Experimental Approaches and Translational Research

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