Prostaglandin E2 produced by late induced COX-2 stimulates hippocampal neuron loss after seizure in the CA3 region

Takemiya, Takako; Maehara, Michiyo; Matsumura, Kiyoshi; Yasuda, Shin; Sugiura, Hiroko; Yamagata, Kanato

doi:10.1016/j.neures.2006.06.003

Cited by 105 publications

(97 citation statements)

References 28 publications

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“…32,33 COX-2 knockout mice were shown to be resistant to neuronal death after KA treatment. 34 Along the same line of the study, we demonstrated that TonEBP heterozygote mice and TonEBP siRNA-treated HT22 cells showed reduced COX-2 expression after KA injection and glutamate treatment, respectively. Consistently, in renal epithelial cells, TonEBP siRNA was also shown to inhibit hypertonicity-induced COX-2 mRNA and protein expression.…”

Section: Discussionmentioning

confidence: 51%

Tonicity-responsive enhancer binding protein haplodeficiency attenuates seizure severity and NF-κB-mediated neuroinflammation in kainic acid-induced seizures

et al. 2014

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Kainic acid (KA)-induced seizures followed by neuronal death are associated with neuroinflammation and blood-brain barrier (BBB) leakage. Tonicity-responsive enhancer binding protein (TonEBP) is known as a transcriptional factor activating osmoprotective genes, and in brain, it is expressed in neuronal nuclei. Thus dysregulation of TonEBP may be involved in the pathology of KA-induced seizures. Here we used TonEBP heterozygote ( þ / À ) mice to study the roles of TonEBP. Electroencephalographic study showed that TonEBP ( þ / À ) mice reduced seizure frequency and severity compared with wild type during KA-induced status epilepticus. Immunohistochemistry and western blotting analysis showed that KA-induced neuroinflammation and BBB leakage were dramatically reduced in TonEBP ( þ / À ) mice. Similarly, TonEBP-specific siRNA reduced glutamate-induced death in HT22 hippocampal neuronal cells. TonEBP haplodeficiency prevented KA-induced nuclear translocation of NF-jB p65 and attenuated inflammation. Our findings identify TonEBP as a critical regulator of neuroinflammation and BBB leakage in KA-induced seizures, which suggests TonEBP as a good therapeutic target.

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Section: Discussionmentioning

confidence: 51%

Tonicity-responsive enhancer binding protein haplodeficiency attenuates seizure severity and NF-κB-mediated neuroinflammation in kainic acid-induced seizures

et al. 2014

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“…Acute pretreatment with PTGS inhibitors such as celecoxib, nimesulide and flurbiprofen has been shown to increase seizure activity in response to excitotoxic doses of KA or pentylenetetrazole [4,61], supporting the suggested role for PTGS in regulation of neuronal excitability. Conversely, PTGS inhibition by genetic or pharmacological means after neuronal damage has been initiated results in neuroprotection [9,15,18,21,26,63]. While this dichotomy is well defined for the studies mentioned above, it has also been demonstrated that mice over expressing a human form of PTGS-2 solely in neurons, had increased KA induced mortality [27].…”

Section: Discussionmentioning

confidence: 99%

“…In addition, the distribution of PTGS-2 in these mice was restricted to neurons thereby making their model difficult to compare to ours which has a universal lack of PTGS-2. Furthermore, the assertion of Takemiya et al [63] that PTGS-2 deficient mice exhibit less neuronal loss after icv KA injections when compared to wild type mice suffers from the lack of both a stereology-based neuronal count [36] and of a demonstrated similarity in the baseline number of neurons in saline exposed PTGS-2 deficient and wild type mice. While we do not dispute the possible involvement of PTGS-2 in determining the extent of neuronal death, our study overwhelmingly supports the observations of those who have demonstrated that acute pharmacological abrogation of PTGS activity before KA injection increases seizure intensity.…”

Section: Discussionmentioning

confidence: 99%

Altered GABAergic neurotransmission is associated with increased kainate-induced seizure in prostaglandin-endoperoxide synthase-2 deficient mice

Toscano

Ueda

Tomita

et al. 2008

Brain Research Bulletin

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Excitotoxicity involves over activation of brain excitatory glutamate receptors and has been implicated in neurological, neurodegenerative and neuropsychiatric diseases. Metabolism of arachidonic acid (AA) through the phospholipase A 2 (PLA 2 )/ prostaglandin-endoperoxide synthase (PTGS) pathway is increased after excitotoxic stimulation. However, the individual roles of the PTGS isoforms in this process are not well established. We assessed the role of the PTGS isoforms in the process of excitotoxicity by exposing mice deficient in either PTGS-1 (PTGS-1 -/-) or PTGS-2 (PTGS-2 -/-) to the rototypic excitotoxin, kainic acid (KA). Seizure intensity and neuronal damage were significantly elevated in KA-exposed PTGS-2 -/-, but not in PTGS-1 -/-, mice. The increased susceptibility was not associated with an alteration in KA receptor binding activity or mediated through the CB1 endocannabinoid receptor. The frequency of spontaneous inhibitory postsynaptic currents (sIPSCs) was decreased in the CA1 pyramidal neurons of PTGS-2 -/-mice, suggesting an alteration of GABAergic function. In wild-type mice, six weeks treatment with the PTGS-2 selective inhibitor celecoxib recapitulated the increased susceptibility to KA-induced excitotoxicity observed in PTGS-2 -/-mice, further supporting the role of PTGS-2 in the excitotoxic process. The increased susceptibility to KA was also associated with decreased brain levels of PGE 2 , a biomarker of PTGS-2 activity. Our results suggest that PTGS-2 activity and its specific products may modulate neuronal excitability by affecting GABAergic neurotransmission. Further, inhibition of PTGS-2 but not PTGS-1, may increase the susceptibility to seizures.

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“…39) In animal models of temporal lobe epilepsy induced by intrahippocampal or intraperitoneal injection of kainic acid (KA), an agonist of non-N-methyl-D-aspartate (non-NMDA) ionotropic glutamate receptors, COX-2 expression was shown to be increased immediately in hippocampal neurons and gradually in nonneuronal cells, such as endothelia and astrocytes, after induction of seizures. 40) The PGE 2 level was also increased in the hippocampus after KA-induced seizures. Late-induced COX-2 produces a large amount of PGE 2 that may facilitate neuronal loss elicited by KA, because a COX-2 inhibitor relieved this neuronal damage.…”

Section: Role Of Mpges-1 In Epilepsymentioning

confidence: 92%

The Role of mPGES-1 in Inflammatory Brain Diseases

Ikeda‐Matsuo

2017

Biological & Pharmaceutical Bulletin

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Prostaglandin E 2 (PGE 2 ) has been thought to be an important mediator of inflammation in peripheral tissues, but recent studies clearly show the involvement of PGE 2 in inflammatory brain diseases. In some animal models of brain disease, the genetic disruption and chemical inhibition of cyclooxygenase (COX)-2 resulted in the reduction of PGE 2 and amelioration of symptoms, and it had been thought that PGE 2 produced by COX-2 may be involved in the progression of injuries. However, COX-2 produces not only PGE 2 , but also some other prostanoids, and thus the protective effects of COX-2 inhibition, as well as severe side effects, may be caused by the inhibition of prostanoids other than PGE 2 . Therefore, to elucidate the role of PGE 2 , studies of microsomal prostaglandin E synthase-1 (mPGES-1), an inducible terminal enzyme for PGE 2 synthesis, have recently been an active area of research. Studies from mPGES-1 deficient mice provide compelling evidence for its role in a variety of inflammatory brain diseases, such as ischemic stroke, Alzheimer's disease and epilepsy, and clues for developing new therapeutic treatments for brain diseases by targeting mPGES-1. Considering that COX inhibitors may non-selectively suppress the production of many types of prostanoids that are essential for normal physiological functioning of the brain and peripheral tissues, as well as induce gastro-intestinal, renal and cardiovascular complications, mPGES-1 inhibitors are expected to be injury-selective and have fewer side-effects when treating human brain diseases. Thus, this paper focuses on recent studies that have demonstrated the involvement of mPGES-1 in pathological brain diseases.

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Prostaglandin E2 produced by late induced COX-2 stimulates hippocampal neuron loss after seizure in the CA3 region

Cited by 105 publications

References 28 publications

Tonicity-responsive enhancer binding protein haplodeficiency attenuates seizure severity and NF-κB-mediated neuroinflammation in kainic acid-induced seizures

Tonicity-responsive enhancer binding protein haplodeficiency attenuates seizure severity and NF-κB-mediated neuroinflammation in kainic acid-induced seizures

Altered GABAergic neurotransmission is associated with increased kainate-induced seizure in prostaglandin-endoperoxide synthase-2 deficient mice

The Role of mPGES-1 in Inflammatory Brain Diseases

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