title: Soluble epoxide hydrolase activity regulates inflammatory responses and seizure generation in two mouse models of temporal lobe epilepsy.
abstract: Neuroinflammation is known to be involved in epileptogenesis with unclear mechanisms. Inhibition of soluble epoxide hydrolase (sEH) seems to offer anti-inflammatory protection to ischemic brain injury in rodents. Thus, it is hypothesized that sEH inhibition might also affect the neuroinflammatory responses caused by epileptic seizures. In the present study, we investigated the involvement of sEH in neuroinflammation, seizure generation and subsequent epileptogenesis using two mouse models of temporal lobe epilepsy. Experimental epileptic seizures were induced by either pilocarpine or electrical amygdala kindling in both wild-type (WT) C57BL/6 mice and sEH knockout (sEH KO) mice. The sEH expression in the hippocampus was detected by immunohistochemistry and Western blot analysis. The effects of the sEH hydrolase inhibitors, 12-(3-adamantan-1-yl-ureido)-dodecanoic acid (AUDA) and N-[1-(1-oxopropyl)-4-piperidinyl]-N'-[4-(trifluoromethoxy) phenyl)-urea (TPPU), and of the genetic deletion of sEH on seizure-induced neuroinflammatory responses and the development of epilepsy were evaluated. In the hippocampus of WT mice, sEH was mainly expressed in astrocytes (GFAP(+)), neurons (NeuN(+)) and scattered microglia (Iba-1(+)) in the regions of CA1, CA3 and dentate gyrus. Expression of sEH was significantly increased on day 7, 14, 21 and 28 after pilocarpine-induced status epilepticus (SE). Administration with sEH inhibitors attenuated the SE-induced up-regulation of interleukin-1β (IL-1β) and interleukin-6 (IL-6), the degradation of EETs, as well as IκB phosphorylation. Following treatment with AUDA, the frequency and duration of spontaneous motor seizures in the pilocarpine-SE mice were decreased and the seizure-induction threshold of the fully kindled mice was increased. Up-regulation of hippocampal IL-1β and IL-6 was found in both WT and sEH KO mice after successful induction of SE. Notably, sEH KO mice were more susceptible to seizures than WT mice. Seizure related neuroinflammation and ictogenesis were attenuated by pharmacological inhibition of sEH enzymatic activity but not by sEH genetic deletion. Therefore, sEH may play an important role in the generation of epilepsy. Furthermore, the effectiveness of AUDA in terms of anti-inflammatory and anti-ictogenesis properties suggests that it may have clinical therapeutic implication for epilepsy in the future, particularly when treating temporal lobe epilepsy.
authors.affiliation: Institute of Physiology, National Yang-Ming University, Taipei, Taiwan; Institute of Brain Science, National Yang-Ming University, Taipei, Taiwan; Brain Research Center, National Yang-Ming University, Taipei, Taiwan; Laboratory of Neurophysiology, Taipei Veterans General Hospital, Taipei, Taiwan.
authors.forename: Yu-Wen
authors.initials: YW
authors.lastname: Hung
authors.affiliation: Institute of Brain Science, National Yang-Ming University, Taipei, Taiwan; Laboratory of Neurophysiology, Taipei Veterans General Hospital, Taipei, Taiwan; Division of Animal Medicine, Animal Technology Laboratories, Agricultural Technology Research Institute, Hsinchu, Taiwan.
authors.forename: Shao-Wen
authors.initials: SW
authors.lastname: Hung
authors.affiliation: Institute of Brain Science, National Yang-Ming University, Taipei, Taiwan; Laboratory of Neurophysiology, Taipei Veterans General Hospital, Taipei, Taiwan.
authors.forename: Yi-Chen
authors.initials: YC
authors.lastname: Wu
authors.affiliation: Institute of Brain Science, National Yang-Ming University, Taipei, Taiwan; Laboratory of Neurophysiology, Taipei Veterans General Hospital, Taipei, Taiwan.
authors.forename: Lin-King
authors.initials: LK
authors.lastname: Wong
authors.affiliation: Institute of Brain Science, National Yang-Ming University, Taipei, Taiwan; Laboratory of Neurophysiology, Taipei Veterans General Hospital, Taipei, Taiwan.
authors.forename: Ming-Tsong
authors.initials: MT
authors.lastname: Lai
authors.affiliation: Institute of Brain Science, National Yang-Ming University, Taipei, Taiwan; School of Medicine, National Yang-Ming University, Taipei, Taiwan; Department of Neurosurgery, Taipei Veterans General Hospital, Taipei, Taiwan.
authors.forename: Yang-Hsin
authors.initials: YH
authors.lastname: Shih
authors.affiliation: Institute of Physiology, National Yang-Ming University, Taipei, Taiwan. Electronic address: tslee@ym.edu.tw.
authors.forename: Tzong-Shyuan
authors.initials: TS
authors.lastname: Lee
authors.affiliation: Institute of Physiology, National Yang-Ming University, Taipei, Taiwan; Institute of Brain Science, National Yang-Ming University, Taipei, Taiwan; Institute of Clinical Medicine, National Yang-Ming University, Taipei, Taiwan; Brain Research Center, National Yang-Ming University, Taipei, Taiwan; School of Medicine, National Yang-Ming University, Taipei, Taiwan; Laboratory of Neurophysiology, Taipei Veterans General Hospital, Taipei, Taiwan; Department of Neurology, Taipei Veterans General Hospital, Taipei, Taiwan. Electronic address: yylin@vghtpe.gov.tw.
authors.forename: Yung-Yang
authors.initials: YY
authors.lastname: Lin
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D004833:Epilepsy, Temporal Lobe / Q000209:etiology / Q000378:metabolism*; D004851:Epoxide Hydrolases / Q000235:genetics / Q000378:metabolism*; D006624:Hippocampus / Q000378:metabolism*; D007249:Inflammation / Q000378:metabolism*; D053583:Interleukin-1beta; D015850:Interleukin-6 / Q000378:metabolism; D007696:Kindling, Neurologic / Q000378:metabolism*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D010862:Pilocarpine; D012640:Seizures / Q000209:etiology / Q000378:metabolism*; D015854:Up-Regulation
chemical_list: D053583:Interleukin-1beta; D015850:Interleukin-6; D010862:Pilocarpine; D004851:Epoxide Hydrolases
keywords: Epilepsy; Neuroinflammation; Proinflammatory cytokines; Soluble epoxide hydrolase