Editorial: Neuroinflammation in acquired epilepsy

Jiang, Jianxiong; Santhakumar, Vijayalakshmi; Zhu, Xinjian

doi:10.3389/fcell.2022.1074537

Cited by 7 publications

(5 citation statements)

References 18 publications

(20 reference statements)

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“…Prolonged seizures can initiate several lines of neuroinflammatory processes that often precede the occurrence of spontaneous seizures and presumably play an essential role in epileptogenesis [ 31 – 34 ]. We next evaluated the effects of mPGES-1 inhibition by PBCH on SE-induced brain inflammation via examining the mRNA expression of a number of inflammation-associated genes in the hippocampus 4 d after pilocarpine-induced SE.…”

Section: Resultsmentioning

confidence: 99%

Transient inhibition of microsomal prostaglandin E synthase-1 after status epilepticus blunts brain inflammation and is neuroprotective

Yasmen

Sluter

et al. 2023

Mol Brain

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Status epilepticus (SE) in humans is characterized by prolonged convulsive seizures that are generalized and often difficult to control. The current antiseizure drugs (ASDs) aim to stop seizures quickly enough to prevent the SE-induced brain inflammation, injury, and long-term sequelae. However, sole reliance on acute therapies is imprudent because prompt treatment may not always be possible under certain circumstances. The pathophysiological mechanisms underlying the devastating consequences of SE are presumably associated with neuroinflammatory reactions, where prostaglandin E2 (PGE2) plays a pivotal role. As the terminal synthase for pathogenic PGE2, the microsomal prostaglandin E synthase-1 (mPGES-1) is rapidly and robustly induced by prolonged seizures. Congenital deletion of mPGES-1 in mice is neuroprotective and blunts gliosis following chemoconvulsant seizures, suggesting the feasibility of mPGES-1 as a potential antiepileptic target. Herein, we investigated the effects of a dual species mPGES-1 inhibitor in a mouse pilocarpine model of SE. Treatment with the mPGES-1 inhibitor in mice after SE that was terminated by diazepam, a fast-acting benzodiazepine, time-dependently abolished the SE-induced PGE2 within the brain. Its negligible effects on cyclooxygenases, the enzymes responsible for the initial step of PGE2 biosynthesis, validated its specificity to mPGES-1. Post-SE inhibition of mPGES-1 also blunted proinflammatory cytokines and reactive gliosis in the hippocampus and broadly prevented neuronal damage in a number of brain areas. Thus, pharmacological inhibition of mPGES-1 by small-molecule inhibitors might provide an adjunctive strategy that can be implemented hours after SE, together with first-line ASDs, to reduce SE-provoked brain inflammation and injury.

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Section: Resultsmentioning

confidence: 99%

Transient inhibition of microsomal prostaglandin E synthase-1 after status epilepticus blunts brain inflammation and is neuroprotective

Yasmen

Sluter

et al. 2023

Mol Brain

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“…22 There is an urgent need for novel treatment options for seizures and epilepsy due to the significant limitations of current antiseizure medications. 23–25…”

Section: Epilepsymentioning

confidence: 99%

“…22 There is an urgent need for novel treatment options for seizures and epilepsy due to the significant limitations of current antiseizure medications. [23][24][25] PGE 2 has long been implicated in facilitating the deleterious effects of seizures. [26][27][28][29] However, the effects of mPGES-1 inhibition on seizures and epilepsy have seldom been explored since most efforts targeting seizure-induced PGE 2 have been focused on COX-2, the enzyme mediating the first step of PGE 2 biosynthesis.…”

Section: Epilepsymentioning

confidence: 99%

The inducible prostaglandin E synthase (mPGES-1) in neuroinflammatory disorders

Sluter

Yasmen

et al. 2023

Exp Biol Med (Maywood)

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The cyclooxygenase (COX)/prostaglandin E2 (PGE2) signaling pathway has emerged as a critical target for anti-inflammatory therapeutic development in neurological diseases. However, medical use of COX inhibitors in the treatment of various neurological disorders has been limited due to well-documented cardiovascular and cerebrovascular complications. It has been widely proposed that modulation of downstream microsomal prostaglandin E synthase-1 (mPGES-1) enzyme may provide more specificity for inhibiting PGE2-elicited neuroinflammation. Heightened levels of mPGES-1 have been detected in a variety of brain diseases such as epilepsy, stroke, glioma, and neurodegenerative diseases. Subsequently, elevated levels of PGE2, the enzymatic product of mPGES-1, have been demonstrated to modulate a multitude of deleterious effects. In epilepsy, PGE2 participates in retrograde signaling to augment glutamate release at the synapse leading to neuronal death. The excitotoxic demise of neurons incites the activation of microglia, which can become overactive upon further stimulation by PGE2. A selective mPGES-1 inhibitor was able to reduce gliosis and the expression of proinflammatory cytokines in the hippocampus following status epilepticus. A similar mechanism has also been observed in stroke, where the overactivation of microglia by PGE2 upregulated the expression and secretion of proinflammatory cytokines. This intense activation of neuroinflammatory processes triggered the secondary injury commonly observed in stroke, and blockade of mPGES-1 reduced infarction size and edema, suppressed induction of proinflammatory cytokines, and improved post-stroke well-being and cognition. Furthermore, elevated levels of PGE2 have been shown to intensify the proliferation of glioma cells, mediate P-glycoprotein expression at the blood-brain barrier (BBB) and facilitate breakdown of the BBB. For these reasons, targeting mPGES-1, the central and inducible enzyme of the COX cascade, may provide a more specific therapeutic strategy for treating neuroinflammatory diseases.

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“…Neuroinflammation can persist even after the initial trigger has resolved ,it can affect neuronal excitability, leads to blood-brain barrier (BBB) dysfunction,impacts on seizure threshold and,contributes to the development and progression of seizures [6]. According to the previous studies, cytokine accumulation and imbalances in epileptic tissue are markers of activated neuroinflammatory processes involving cerebral residents and recruited immune cells [7,8]. COX pathway metabolites such as prostaglandins, majorly PGE2, are known that could influence central neural inflammatory pathways and interfere mechanisms of epileptogenesis [9].…”

Section: Introductionmentioning

confidence: 99%

Prostaglandin E2 as neuroinflammatory target in childhood resistant epilepsies

Gakharia,

Bakhtadze,

Khachapuridze

et al. 2024

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Aim: Childhood epilepsies are a diverse group of neurological disorders with a multifaceted clinical course caused by a range of aetiological factors. Despite new Anti Seizure Drugs (ASDs), drug resistance remains a significant hurdle in treatment. Growing evidence links epilepsy to inflammatory processes, especially in drug-resistant cases. A number of neuroinflammatory pathways involving cytokines have been identified in the pathogenesis of drug resistant epilepsy, including the axis of Cox2-PGE2-Prostaglandin E2 receptor 1 that has been shown to affect blood-brain barrier function, and drug pharmacokinetics through upregulation of multidrug effluxers. We measured the plasma PGE2 levels aiming to determine PGE2 importance in epilepsy-associated inflammation and antiepileptic drug (AED) response for the patients with different types of epilepsy .Methods: a prospective review of clinical and paraclinical data of study group (Group 1), including patients with epilepsy who had ongoing long term follow-up in two subgroups: Group 1A-Patients diagnosed with epilepsy -seizure-free on AED therapy, Group 1B-patients with refractory epilepsy and healthy control group (Group2). Serum samples tested for PGE2 levels(interquartile ranges/pg/ml) by the enzyme-linked immunosorbent assay (ELISA).Results: Measured serum PGE2 the median interquartile ranges (IQR) were higher and in broader ranges for epilepsy patients all together 512 pg/ml (324.5-970.0 )compared to healthy controls 406 pg/ml (278.7-541.4) , but not significantly different across the epilepsy study groups (p>0.05). Only Valproate responders showed reduced PGE2 mean IQR 490 pg/ml. Conclusions: Our findings align with preclinical models, suggesting a potential target on molecular basis for overcoming drug resistance, which is a major challenge and key toward precision medicine in epilepsy management.

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Editorial: Neuroinflammation in acquired epilepsy

Cited by 7 publications

References 18 publications

Transient inhibition of microsomal prostaglandin E synthase-1 after status epilepticus blunts brain inflammation and is neuroprotective

Transient inhibition of microsomal prostaglandin E synthase-1 after status epilepticus blunts brain inflammation and is neuroprotective

The inducible prostaglandin E synthase (mPGES-1) in neuroinflammatory disorders

Prostaglandin E2 as neuroinflammatory target in childhood resistant epilepsies

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