Cyclooxygenase-2 expression in the hippocampus of genetically epilepsy susceptible El mice was increased after seizure

doi:10.1016/S0006-8993(01)02019-4

Brain Research

Volume 894, Issue 2, 16 March 2001, Pages 332-335

https://doi.org/10.1016/S0006-8993(01)02019-4 Get rights and content

Abstract

It has been suggested that cyclooxygenase (COX)-2 and prostaglandin play a role in epilepsy. We studied the expression of COX-2 in the hippocampus and the effect of oral administration of indomethacin, a COX inhibitor, on seizure activity in genetically seizure-susceptible El mice. COX-2 protein significantly increased in the hippocampi of El mice after epileptic seizure. Indomethacin did shorten the duration from seizure onset to full recovery in El mice although the threshold and the duration of seizure were not changed.

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Cited by (49)

Differential regulation of gene expression pathways with dexamethasone and ACTH after early life seizures
2022, Neurobiology of Disease
Citation Excerpt :
In contrast, the gene Ptgs2 (Cox2) is downregulated by ACTH post-ELS. This gene has been actively studied in the context of seizure disorders and other neurological diseases for the past two decades (Okada et al., 2001; Chen et al., 2002; Almalki et al., 2014). In 2002, Chen and colleagues observed that selective COX2 inhibitors decreased membrane excitability and decreased back propagation of action potential-induced Ca2+ influx, a key feature of LTP.
Early-life seizures (ELS) are associated with persistent cognitive deficits such as ADHD and memory impairment. These co-morbidities have a dramatic negative impact on the quality of life of patients. Therapies that improve cognitive outcomes have enormous potential to improve patients' quality of life. Our previous work in a rat flurothyl-induction model showed that administration of adrenocorticotropic hormone (ACTH) at time of seizure induction led to improved learning and memory in the animals despite no effect on seizure latency or duration. Administration of dexamethasone (Dex), a corticosteroid, did not have the same positive effect on learning and memory and has even been shown to exacerbate injury in a rat model of temporal lobe epilepsy. We hypothesized that ACTH exerted positive effects on cognitive outcomes through beneficial changes to gene expression and proposed that administration of ACTH at seizure induction would return gene-expression in the brain towards the normal pattern of expression in the Control animals whereas Dex would not. Twenty-six Sprague-Dawley rats were randomized into vehicle- Control, and ACTH-, Dex-, and vehicle- ELS. Rat pups were subjected to 60 flurothyl seizures from P5 to P14. After seizure induction, brains were removed and the hippocampus and PFC were dissected, RNA was extracted and sequenced, and differential expression analysis was performed using generalized estimating equations. Differential expression analysis showed that ACTH pushes gene expression in the brain back to a more normal state of expression through enrichment of pathways involved in supporting homeostatic balance and down-regulating pathways that might contribute to excitotoxic cell-damage post-ELS.
Galangin Prevents Increased Susceptibility to Pentylenetetrazol-Stimulated Seizures by Prostaglandin E2
2019, Neuroscience
Citation Excerpt :
However, despite the important role of PGE2 in controlling neuronal excitability, little is known about its functions during seizures. Therefore, it is appropriate to propose that COX-2 overexpression, as demonstrated in epileptic patients and experimental models (Okada et al., 2001; Desjardins et al., 2003), may raise PGE2 levels and contribute to the appearance and/or increase in the number of crises (Takemiya et al., 2003). In agreement, Oliveira et al. (2008b) demonstrated that the anti-inflammatory celecoxib (selective COX-2 inhibitor) increased latency to PTZ-induced seizures in rats, and this protective effect was reversed by administrating intracerebroventricular PGE2 [10 ng/2 μl (i.c.v.)].
Epilepsy is one of the most common chronic neurological diseases. It is characterized by recurrent epileptic seizures, where one-third of patients are refractory to existing treatments. Evidence revealed the association between neuroinflammation and increased susceptibility to seizures since there is a pronounced increase in the expression of key inflammatory mediators, such as prostaglandin E₂ (PGE₂), during seizures. The purpose of this study was to investigate whether PGE₂ increases susceptibility to pentylenetetrazol-induced (PTZ) seizures. Subsequently, we evaluated if the flavonoid isolated from the plant Piper aleyreanum (galangin) presented any anticonvulsive effects. Our results demonstrated that the group treated with PGE₂ increased susceptibility to PTZ and caused myoclonic and generalized seizures, which increased seizure duration and electroencephalographic wave amplitudes. Furthermore, treatment with PGE₂ and PTZ increased IBA-1 (microglial marker), GFAP (astrocytic marker), 4-HNE (lipid peroxidation marker), VCAM-1 (vascular cell adhesion molecule 1), and p-PKAIIα (phosphorylated cAMP-dependent protein kinase) immunocontent. Indeed, galangin prevented behavioral and electroencephalographic seizures, reactive species production, decreased microglial and astrocytic immunocontent, as well as decreased VCAM-1 immunocontent and p-PKA/PKA ratio induced by PGE₂/PTZ. Therefore, this study suggests galangin may have an antagonizing role on PGE₂-induced effects, reducing cerebral inflammation and protecting from excitatory effects evidenced by administrating PGE₂ and PTZ. However, further studies are needed to investigate the clinical implications of the findings and their underlying mechanisms.
Maintenance of the Innate Seizure Threshold by Cyclooxygenase-2 is Not Influenced by the Translational Silencer, T-cell Intracellular Antigen-1
2018, Neuroscience
Activity of neuronal cyclooxygenase-2 (COX-2), a primary source of PG synthesis in the normal brain, is enhanced by excitatory neurotransmission and this is thought to be involved in seizure suppression. Results herein showing that the incidence of pentylenetetrazole (PTZ)-induced convulsions is suppressed in transgenic mice overexpressing COX-2 in neurons support this notion. T-cell intracellular antigen-1 (TIA-1) is an mRNA binding protein that is known to bind to COX-2 mRNA and repress its translation in non-neuronal cell types. An examination of the expression profile of TIA-1 protein in the normal brain indicated that it is expressed broadly by neurons, including those that express COX-2. However, whether TIA-1 regulates COX-2 protein levels in neurons is not known. The purpose of this study was to test the possibility that deletion of TIA-1 increases basal COX-2 expression in neurons and consequently raises the seizure threshold. Results demonstrate that neither the basal nor seizure-induced expression profiles of COX-2 were altered in mice lacking a functional TIA-1 gene suggesting that TIA-1 does not contribute to regulation of COX-2 protein expression in neurons. The acute PTZ-induced seizure threshold was also unchanged in mice lacking TIA-1 protein, indicating that this RNA binding protein does not influence the innate seizure threshold. Nevertheless, the results raise the possibility that the level of neuronal COX-2 expression may be a determinant of the innate seizure threshold and suggest that a better understanding of the regulation of COX-2 expression in the brain could provide new insight into the molecular mechanisms that suppress seizure induction.
Antiepileptogenic effects of the selective COX-2 inhibitor etoricoxib, on the development of spontaneous absence seizures in WAG/Rij rats
2015, Brain Research Bulletin
Different data suggest the involvement of specific inflammatory pathways in the pathogenesis of epilepsy. Cyclooxygenase (COX), which catalyses the production of pro-inflammatory prostaglandins, may play a significant role in seizure-induced neuroinflammation and neuronal hyperexcitability. COX-2 is constitutively expressed in the brain and also increased during/after seizures. COX-2 inhibitors may thus attenuate inflammation associated with brain disorders. We studied whether early long-term treatment (17 consecutive weeks starting from 45 days postnatal age) with the non-steroidal anti-inflammatory drug etoricoxib (10 mg/kg/day per os), a selective COX-2 inhibitor, was able to prevent/reduce the development of absence seizures in WAG/Rij rats, a recognized animal model of absence epilepsy and epileptogenesis. Drug effects on the incidence, duration and properties of absence seizure spike-wave discharges (SWDs) were measured both 1 and 5 months after treatment withdrawal; furthermore, the acute effects of etoricoxib on SWDs in 6-month-old WAG/Rij rats were measured. Early long-term treatment (ELTT) with etoricoxib led to an ∼40% long-lasting (5 months) reduction in the development of spontaneous absence seizures in adult WAG/Rij rats thus exhibiting antiepileptogenic effects. Acutely administered etoricoxib (10 and 20 mg/kg i.p.) also had anti-absence properties, significantly reducing the number and duration of SWDs by ∼50%. These results confirm the antiepileptogenic effects of COX-2 inhibitors and suggest the possible role of COX-2, prostaglandin synthesis and consequent neuroinflammation in the epileptogenic process underlying the development of absence seizures in WAG/Rij rats.
Commentary on Kaushik et al.: Prostaglandin D<inf>2</inf> is crucial for seizure suppression and postictal sleep. Novel evidence supporting a role for prostanoid receptors in seizure control
2014, Experimental Neurology
Accumulating clinical and experimental evidence suggests a role for prostaglandins (PGs) in epilepsy and isolated seizures. Prostaglandin levels are increased in the hippocampus of epileptic patients and in the cerebrospinal fluid of children with febrile seizures. Moreover, increased PGD₂, PGE₂ and PGF_2α levels are found in the brain after chemically-induced seizures and in spontaneously epileptic mice. However, whether prostaglandins facilitate or decrease seizures has been a matter of debate in the literature. Both pro- and anticonvulsant activities have been described for most of prostaglandins, except for PGD₂ and DP receptor agonists, for which a consistent anticonvulsant action has been reported. The study by Kaushik and colleagues elegantly extends this view by showing that hematopoietic PGD synthase (H-PGDS) and DP₁ receptors are essential for seizure suppression and that lipocalin-type prostaglandin D synthase (L-PGDS)/PGD₂/DP₁ system regulates sleep that follows PTZ-induced seizures using knockout animals. This commentary discusses the experimental approach of the studies that have implicated prostaglandins and their receptors in seizures, the interesting approach and results of Kaushik and colleagues, and the challenges of considering PGD₂ signaling as a therapeutic target in epilepsy.
Aspirin attenuates spontaneous recurrent seizures and inhibits hippocampal neuronal loss, mossy fiber sprouting and aberrant neurogenesis following pilocarpine-induced status epilepticus in rats
2012, Brain Research
Citation Excerpt :
COXs are rate-limiting enzymes in PGs synthesis and are major targets of nonsteroidal anti-inflammatory drugs (NSAIDs) (Takemiya et al., 2007). An up-regulation of hippocampal COX-2 expression was observed in epileptic rats and in patients with TLE (Desjardins et al., 2003; Okada et al., 2001). More recent data indicates that the expression of COX-1 in microglia was also enhanced in the hippocampus and areas around the third ventricle during the progression of seizures (Tanaka et al., 2009).
Accumulating data suggest that inflammation may contribute to epileptogenesis in experimental models as well as in humans. However, whether anti-inflammatory treatments can prevent epileptogenesis still remains controversial. Here, we examined the anti-epileptogenic effect and possible mechanisms of aspirin, a non-selective Cyclooxygenase (COX) inhibitor, in a rat model of lithium-pilocarpine-induced status epilepticus (SE). Epileptic rats were treated with aspirin (20 mg/kg) at 0 h, 3 h, or 24 h after the termination of SE, followed by once daily treatment for the subsequent 20 days. We found that aspirin treatment significantly reduced the frequency and duration of spontaneous recurrent seizures during the chronic epileptic phase. Hippocampal neuronal loss five weeks after SE was also attenuated in the CA1, CA3 and hilus following aspirin administration. Furthermore, the aberrant migration of newly generated granule cells and the formation of hilar basal dendrites were prevented by aspirin. Treatment with aspirin starting at 3 h or 24 h after SE also suppressed the development of mossy fiber sprouting. These findings suggest the possibility of a relative broad time-window for aspirin intervention in the epileptogenic process after injury. Aspirin may serve as a potential adjunctive therapy for individuals susceptible to chronic epilepsy.

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Short communicationCyclooxygenase-2 expression in the hippocampus of genetically epilepsy susceptible El mice was increased after seizure

Abstract

Brain Res.

Brain Res.

Prog. Brain Res.

J. Lipid Mediat. Cell Signal.

Lancet

Am. J. Pathol.

J. Biol. Chem.

Life Sci.

Blood

Short communication
Cyclooxygenase-2 expression in the hippocampus of genetically epilepsy susceptible El mice was increased after seizure