The expression of inflammatory markers and their potential influence on efflux transporters in drug‐resistant mesial temporal lobe epilepsy tissue

Weidner, Lora D.; Kannan, Pavitra; Mitsios, Nicholas; Kang, Sun J.; Hall, Matthew D.; Theodore, William H.; Innis, Robert B.; Mulder, Jan

doi:10.1111/epi.14505

Cited by 48 publications

(36 citation statements)

References 30 publications

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“…Pre-treatment with the transcriptional as well as translational inhibitors showed no reduction in glutamate-induced COX-2 activity confirming the effect of glutamate on COX-2 to be independent of any transcriptional and translational changes. Contrary to our findings, previous preclinical 34,37,38 and clinical [51][52][53][54] studies have reported overexpression of COX-2 in brain and brain endothelial cells following seizures or in epilepsy. Epileptogenesis is a complex, multifactorial mechanism involving alterations in inhibitory and excitatory neurotransmitters, ion channels, neuroinflammatory pathways, etc., therefore, the effect on a particular gene may differ with the type of convulsive challenge to in vitro and in vivo model systems.…”

Section: Discussioncontrasting

confidence: 99%

Downregulation of peripheral PTGS2/COX-2 in response to valproate treatment in patients with epilepsy

Rawat

Kutum

Kukal

et al. 2020

Sci Rep

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Antiepileptic drug therapy has significant inter-patient variability in response towards it. The current study aims to understand this variability at the molecular level using microarray-based analysis of peripheral blood gene expression profiles of patients receiving valproate (VA) monotherapy. Only 10 unique genes were found to be differentially expressed in VA responders (n = 15) and 6 genes in the nonresponders (n = 8) (fold-change >2, p < 0.05). PTGS2 which encodes cyclooxygenase-2, COX-2, showed downregulation in the responders compared to the non-responders. PTGS2/COX-2 mRNA profiles in the two groups corresponded to their plasma profiles of the COX-2 product, prostaglandin E 2 (PGE 2). Since COX-2 is believed to regulate P-glycoprotein (P-gp), a multidrug efflux transporter over-expressed at the blood-brain barrier (BBB) in drug-resistant epilepsy, the pathway connecting COX-2 and P-gp was further explored in vitro. Investigation of the effect of VA upon the brain endothelial cells (hCMEC/D3) in hyperexcitatory conditions confirmed suppression of COX-2-dependent P-gp upregulation by VA. Our findings suggest that COX-2 downregulation by VA may suppress seizure-mediated P-gp upregulation at the BBB leading to enhanced drug delivery to the brain in the responders. Our work provides insight into the association of peripheral PTGS2/COX-2 expression with VA efficacy and the role of COX-2 as a potential therapeutic target for developing efficacious antiepileptic treatment. Epilepsy, a multifactorial neurological disease, affects about 69 million people worldwide constituting nearly 1% of the world population 1. The treatment is primarily based on symptomatic pharmacological interventions i.e. antiepileptic drug (AED) therapy which controls the frequency of seizures in the patients. Despite the availability of appropriate therapy, there is significant inter-individual variability in AED response. Nearly 40-50% of the patients with epilepsy (PWE) fail to respond to their first AED monotherapy 2,3 with 30% cases showing refractoriness 4. This non-responsiveness to AEDs encouraged researchers to identify the predictors of poor response in PWE. Clinical factors such as early age at onset, higher pretreatment seizure frequency, cryptogenic epilepsy, brain neuroanatomic abnormality, etc. have previously been observed to be potential predictors of poor response to prescribed AEDs 3,5. Several studies also investigated the pharmacogenetics of AEDs and suggested the involvement of various drug-metabolizing enzymes (CYPs), drug transporters (ABC transporters), and drug target genes (ion-channels in brain) in deciding treatment outcome, however, remained inconclusive due to the inconsistency in their findings and failure of replication in different populations 6. One reason behind this failure could be the multifactorial nature of the disease which involves genome-environment interactions and therefore limits the independent use of genetics in studying AED response 6-8. Since any change in genetic or environmental factors

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Section: Discussioncontrasting

confidence: 99%

Downregulation of peripheral PTGS2/COX-2 in response to valproate treatment in patients with epilepsy

Rawat

Kutum

Kukal

et al. 2020

Sci Rep

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“…BBB dysfunction is associated with Pgp induction in brain vessels and astrocytes and with increased COX-2 protein and prostaglandin (PG) E2 levels in the same epileptogenic regions (Bauer et al, 2008;Zibell et al, 2009;Schlichtiger et al, 2010;van Vliet et al, 2010). A strict association between COX-2 expression in neurons and glia, COX-1 expression in microglia, and increased Pgp and BCRP expression in microvessels was recently reported in surgical brain tissue from patients with drug-resistant mesial TLE (Weidner et al, 2018). The EP1 receptor (EP1R) for PGE2 seems to be a key factor mediating the COX-2 induced upregulation of Pgp.…”

Section: H Neuroinflammation and Blood-brain Barrier Dysfunction As mentioning

confidence: 92%

Drug Resistance in Epilepsy: Clinical Impact, Potential Mechanisms, and New Innovative Treatment Options

et al. 2020

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Significance Statement-Drug resistance provides a major challenge in epilepsy management. Here, we will review the current understanding of the molecular, genetic, and structural mechanisms of drug resistance in epilepsy and discuss how the problem might be overcome. 608 Löscher et al. Adapted from Rogawski and Löscher (2004), Rogawski et al. (2016), and Sills and Rogawski (2020) Molecular target ASDs that act on target Voltage-gated ion channels Voltage-gated sodium channels Phenytoin, fosphenytoin, a carbamazepine, oxcarbazepine, b eslicarbazepine acetate, c lamotrigine, lacosamide; possibly topiramate, zonisamide, rufinamide Voltage-gated calcium channels (T-type) Ethosuximide Voltage-gated potassium channels (K v 7) Retigabine (ezogabine) GABA-mediated inhibition GABA A receptors Phenobarbital, primidone, stiripentol, benzodiazepines, (including diazepam, lorazepam, midazolam and clonazepam), possibly topiramate, felbamate, retigabine (ezogabine) GAT1 GABA transporter Tiagabine GABA transaminase Vigabatrin Glutamic acid decarboxylase Possibly valproate, gabapentin, pregabalin Presynaptic release machinery SV2A Levetiracetam, brivaracetam a2d subunit of calcium channels Gabapentin, pregabalin Ionotropic glutamate receptors AMPA receptor Perampanel Carbonic anhydratase inhibition Acetazolamide, topiramate, zonisamide, possibly lacosamide Disease-specific mTORC1 signaling d Everolimus Lysosomal enzyme replacement e Cerliponase alfa (recombinant tripeptidyl peptidase 1) Mixed/unknown Valproate, felbamate, topiramate, zonisamide, rufinamide, adrenocorticotrophin (ACTH), cannabidiol, cenobamate AMPA, a-amino-3-hydroxy-5-methyl-4-isoxazole-propionate. a Fosphenytoin is a prodrug for phenytoin. b Oxcarbazepine serves largely as a prodrug for licarbazepine, mainly S-licarbazepine. c Eslicarbarbazepine acetate is a prodrug for S-licarbazepine. d In patients with epilepsy because of tuberous sclerosis complex (TSC). e In patients with epilepsy because of neuronal ceroid lipofuscinosis type 2.

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“…TSPO PET has been used to monitor neuroinflammation in numerous preclinical models and clinical cases of neurologic disease and injury (Dupont et al, 2017;Owen and Matthews, 2011), including epilepsy (Bertoglio et al, 2017). These studies have demonstrated that the contribution of different cell types to the TSPO PET signal can vary widely across diseases and models (Lavisse et al, 2012;Nguyen et al, 2018;Weidner et al, 2018;Yamasaki et al, 2017), highlighting the need to validate TSPO PET data to histological characterization neuroinflammation in individual models. There are currently no data evaluating the correspondence of TSPO PET imaging to histologic indices of neuroinflammation in any model of acute OP intoxication.…”

mentioning

confidence: 99%

TSPO PET Using [18F]PBR111 Reveals Persistent Neuroinflammation Following Acute Diisopropylfluorophosphate Intoxication in the Rat

Hobson

Rowland

Sisó

et al. 2019

Toxicological Sciences

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Acute intoxication with organophosphates (OPs) can trigger status epilepticus followed by persistent cognitive impairment and/or electroencephalographic abnormalities. Neuroinflammation is widely posited to influence these persistent neurological consequences. However, testing this hypothesis has been challenging, in part because traditional biometrics preclude longitudinal measures of neuroinflammation within the same animal. Therefore, we evaluated the performance of noninvasive positron emission tomography (PET), using the translocator protein (TSPO) radioligand [18F]PBR111 against classic histopathologic measures of neuroinflammation in a preclinical model of acute intoxication with the OP diisopropylfluorophosphate (DFP). Adult male Sprague Dawley rats administered pyridostigmine bromide (0.1 mg/kg, im) 30 min prior to administration of DFP (4 mg/kg, sc), atropine sulfate (2 mg/kg, im) and 2-pralidoxime (25 mg/kg, im) exhibited moderate-to-severe seizure behavior. TSPO PET performed prior to DFP exposure and at 3, 7, 14, 21, and 28 days postexposure revealed distinct lesions, as defined by increased standardized uptake values (SUV). Increased SUV showed high spatial correspondence to immunohistochemical evidence of neuroinflammation, which was corroborated by cytokine gene and protein expression. Regional SUV metrics varied spatiotemporally with days postexposure and correlated with the degree of neuroinflammation detected immunohistochemically. Furthermore, SUV metrics were highly correlated with seizure severity, suggesting that early termination of OP-induced seizures may be critical for attenuating subsequent neuroinflammatory responses. Normalization of SUV values to a cerebellar reference region improved correlations to all outcome measures and seizure severity. Collectively, these results establish TSPO PET using [18F]PBR111 as a robust, noninvasive tool for longitudinal monitoring of neuroinflammation following acute OP intoxication.

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The expression of inflammatory markers and their potential influence on efflux transporters in drug‐resistant mesial temporal lobe epilepsy tissue

Cited by 48 publications

References 30 publications

Downregulation of peripheral PTGS2/COX-2 in response to valproate treatment in patients with epilepsy

Downregulation of peripheral PTGS2/COX-2 in response to valproate treatment in patients with epilepsy

Drug Resistance in Epilepsy: Clinical Impact, Potential Mechanisms, and New Innovative Treatment Options

TSPO PET Using [18F]PBR111 Reveals Persistent Neuroinflammation Following Acute Diisopropylfluorophosphate Intoxication in the Rat

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