Tissue Expressions of Soluble Human Epoxide Hydrolase-2 Enzyme in Patients with Temporal Lobe Epilepsy

Ahmedov, Merdin Lyutviev; Kemerdere, Rahşan; Baran, Oğuz; İnal, Berrin Berçik; Gümüş, Alper; Coşkun, Cihan; Yenı, Seher Naz; Eren, Bülent; Uzan, Mustafa; Tanrıverdi, Taner

doi:10.1016/j.wneu.2017.06.137

Cited by 7 publications

(4 citation statements)

References 17 publications

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“…The study shows that sEH is extensively expressed in the central nervous system [12]. The expression of sEH protein has been found to be increased in neurological and psychiatric diseases including epilepsy, Parkinson's disease, Alzheimer's disease, depression, bipolar disorder, schizophrenia, and autism-like spectrum disease [15,[24][25][26]9]. However, the enzyme activity of sEH sometimes showed controversial results [27].…”

Section: Discussionmentioning

confidence: 99%

“…Studies indicate that sEH has been involved in the pathological process of neurological diseases [14]. In a study of 20 patients underwent anterior temporal lobe resection due to temporal lobe epilepsy, the level of sEH is signi cantly higher in the temporal cortex of patients with epilepsy than control group [15]. The inhibitors of sEH have been demonstrated to have anticonvulsant effects on spontaneous recurrent seizures (SRS) and antidepressant effects on epilepsy-associated depression in the pilocarpine induced rodent epilepsy models [16,17].…”

Section: Introductionmentioning

confidence: 99%

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Inhibiting the soluble epoxide hydrolase increases the EpFAs and ERK1/2 expression in the hippocampus of LiCl-pilocarpine post-status epilepticus rat model

Weibin¹,

Yan²,

Wang³

et al. 2021

Preprint

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Purpose This study aimed to investigate the enzyme activity of soluble epoxide hydrolase (sEH) and quantify metabolic substrates i.e. epoxygenated fatty acids (EpFAs) and products of sEH in the hippocampus after administering TPPU [1-trifluoromethoxyphenyl-3-(1-propionylpiperidin-4-yl)urea], the inhibitor of sEH, and further explored whether the extracellular signal-activated protein kinase 1/2 (ERK1/2) was involved in the anti-seizure effect of TPPU in the lithium chloride (LiCl)-pilocarpine induced post-status epilepticus (SE) rat model. Methods The rats were intraperitoneally (I.P.) injected with LiCl and pilocarpine to induce SE and then spontaneous recurrent seizures (SRS) were observed. Rats were randomly assigned into SRS + 0.1 TPPU group (intragastrically administering 0.1 mg/kg/d TPPU), SRS + PEG 400 group (administering the vehicle instead), and Control group. Enzyme-linked immunosorbent assay, Western-blot analysis, and ultra-high-performance liquid chromatography/mass spectrometry (LC/MS) were performed to measure the enzyme activity of sEH, the protein level of sEH and ERK1/2, and the concentration of TPPU and polyunsaturated fatty acids (PUFAs) metabolisms in the hippocampus. Results The frequency of SRS that equal to or greater than Racine 3 degree ranged from 0 to 19 every week in the SRS + PEG 400 group comparing to 0 to 5 every week in the SRS + 0.1 TPPU group. The enzyme activity and protein level of sEH was significantly increased in the SRS + PEG400 group compared with the Control group. After administering TPPU, the concentration of TPPU in the hippocampus was 10.94 ± 4.37 nmol/kg; the enzyme level of sEH was significantly decreased in the LiCl-pilocarpine-induced post-SE rat model, however, the protein level of sEH did not decrease significantly; the regioisomers 8,9-, 11,12-, and 14,15-EETs, the sums of EETs, the ratio of EETs/DHETs, and other EpFAs including 16(17) EpDPA and the ratio of 19(20)-EpDPA/19,20-DiHDPA in the hippocampus were significantly increased. In addition, the ratio of p-ERK1/2 to ERK1/2 in the hippocampus was significantly increased after TPPU administration either. Conclusion We demonstrated that inhibiting sEH with TPPU increased the levels of EETs and some other EpFAs and expression of ERK1/2 in the hippocampus of LiCl-pilocarpine-induced post-SE rat model, indicating the cellular mechanism of EETs through ERK1/2 pathway might be responsible for the anti-seizure effect of TPPU.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Inhibiting the soluble epoxide hydrolase increases the EpFAs and ERK1/2 expression in the hippocampus of LiCl-pilocarpine post-status epilepticus rat model

Weibin¹,

Yan²,

Wang³

et al. 2021

Preprint

View full text Add to dashboard Cite

show abstract

“…The applications of sEHIs in epilepsy hold promise, but clinical translation is lacking. In a study of 20 patients with temporal lobe epilepsy, sEH enzyme levels are increased compared to the control group (110). Furthermore, seizure duration and frequency correlate with sEH level (110).…”

Section: Other Neurological Disorders and Seh Epilepsymentioning

confidence: 95%

“…In a study of 20 patients with temporal lobe epilepsy, sEH enzyme levels are increased compared to the control group (110). Furthermore, seizure duration and frequency correlate with sEH level (110). This suggests that there is a niche for sEHI intervention in humans, but more studies must be conducted to better elucidate the role of sEH in epilepsy.…”

Section: Other Neurological Disorders and Seh Epilepsymentioning

confidence: 99%

Humble beginnings with big goals: Small molecule soluble epoxide hydrolase inhibitors for treating CNS disorders

Zarriello

Tuazon

Corey

et al. 2019

Progress in Neurobiology

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Soluble epoxide hydrolase (sEH) degrades epoxides of fatty acids including epoxyeicosatrienoic acid isomers (EETs), which are produced as metabolites of the cytochrome P450 branch of the arachidonic acid pathway. EETs exert a variety of largely beneficial effects in the context of inflammation and vascular regulation. sEH inhibition is shown to be therapeutic in several cardiovascular and renal disorders, as well as in peripheral analgesia, via the increased availability of anti-inflammatory EETs. The success of sEH inhibitors in peripheral systems suggests their potential in targeting inflammation in the central nervous system (CNS) disorders. Here, we describe the current roles of sEH in the pathology and treatment of CNS disorders such as stroke, traumatic brain injury, Parkinson's disease, epilepsy, cognitive impairment, dementia and depression. In view of the robust anti-inflammatory effects of stem cells, we also outlined the potency of stem cell treatment and sEH inhibitors as a combination therapy for these CNS disorders. This review highlights the gaps in current knowledge about the pathologic and therapeutic roles of sEH in CNS disorders, which should guide future basic science research towards translational and clinical applications of sEH inhibitors for treatment of neurological diseases.

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New and Emerging Antiepileptic Drugs

Witkin

Golani

Smith

2021

Burger's Medicinal Chemistry and Drug Discovery

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This article provides the biologist, chemist, and clinician with an overview into currently existing epilepsy medicines, an appreciation of those currently in development, and a glimpse at future possibilities. The discovery and development of antiepileptic drugs with improved efficacy and side‐effect dimensions are urgently needed. We discuss various strategies for discovering new antiepileptic drugs. We then provide summary data on the mechanisms of action, efficacy, and tolerability of some of the newer third‐generation antiepileptic drugs – eslicarbazepine, brivaracetam, retigabine, lacosamide, and perampanel. Additional compounds that are currently in development for epilepsy are also reviewed. These include the novel α‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazolepropionic acid (AMPA) receptor antagonists CERC‐611 and JNJ‐55511118 that are first‐in‐class drugs blocking only those AMPA receptors associated with the auxiliary protein TAPP γ‐8. The GABA A (α2/3)‐selective compounds, KRM‐II‐81, MP‐III‐080, and PF‐06372865 hold additional promise and potential advantage over nonselective GABA A receptor modulators. The developmental status of another positive allosteric modulator of GABA A receptors, the neuroactive steroid ganaxolone, is also summarized. In addition, two mGlu2 receptor modulators, JNJ‐40411813 and LY2812223 are discussed. Finally, initial data on cannabidiol, anakinra, and padsevonil are reviewed. Literature data derived from studies on both human epileptic tissue and rodent seizure modeling were utilized to glean several compelling novel drug targets for consideration in future antiepileptic drug discovery programs. Thus, in the past decade, key advances have been made that are benefiting the epileptic patient community. The current compounds in development and new drug targets give additional promise of improved antiepileptic drugs.

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Tissue Expressions of Soluble Human Epoxide Hydrolase-2 Enzyme in Patients with Temporal Lobe Epilepsy

Cited by 7 publications

References 17 publications

Inhibiting the soluble epoxide hydrolase increases the EpFAs and ERK1/2 expression in the hippocampus of LiCl-pilocarpine post-status epilepticus rat model

Inhibiting the soluble epoxide hydrolase increases the EpFAs and ERK1/2 expression in the hippocampus of LiCl-pilocarpine post-status epilepticus rat model

Humble beginnings with big goals: Small molecule soluble epoxide hydrolase inhibitors for treating CNS disorders

New and Emerging Antiepileptic Drugs

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