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J Biomed Sci. 2015 Jun 24;22:46. doi: 10.1186/s12929-015-0157-8.

Peripheral inflammation increases seizure susceptibility via the induction of neuroinflammation and oxidative stress in the hippocampus.

Author information

1
Department of Biological Sciences, National Sun Yat-sen University, Kaohsiung, 804, Taiwan. yhho@vghks.gov.tw.
2
Division of Neurology, Kaohsiung Veterans General Hospital, Kaohsiung, 813, Taiwan. yhho@vghks.gov.tw.
3
Division of Neurology, Kaohsiung Veterans General Hospital, Kaohsiung, 813, Taiwan. ytlin@vghks.gov.tw.
4
Center for Translational Research in Biomedical Sciences, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, 833, Taiwan. wuchihwei@hotmail.com.
5
Center for Translational Research in Biomedical Sciences, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, 833, Taiwan. umeichao@yahoo.com.tw.
6
Department of Physiology and Institute of Basic Medical Sciences, National Cheng Kung University, Tainan, 701, Taiwan. aywchang@mail.ncku.edu.tw.
7
Department of Biological Sciences, National Sun Yat-sen University, Kaohsiung, 804, Taiwan. jchan@adm.cgmh.org.tw.
8
Center for Translational Research in Biomedical Sciences, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, 833, Taiwan. jchan@adm.cgmh.org.tw.

Abstract

BACKGROUND:

Neuroinflammation with activation of microglia and production of proinflammatory cytokines in the brain plays an active role in epileptic disorders. Brain oxidative stress has also been implicated in the pathogenesis of epilepsy. Damage in the hippocampus is associated with temporal lobe epilepsy, a common form of epilepsy in human. Peripheral inflammation may exacerbate neuroinflammation and brain oxidative stress. This study examined the impact of peripheral inflammation on seizure susceptibility and the involvement of neuroinflammation and oxidative stress in the hippocampus.

RESULTS:

In male, adult Sprague-Dawley rats, peripheral inflammation was induced by the infusion of Escherichia coli lipopolysaccharide (LPS, 2.5 mg/kg/day) into the peritoneal cavity for 7 days via an osmotic minipump. Pharmacological agents were delivered via intracerebroventricular (i.c.v.) infusion with an osmotic minipump. The level of cytokine in plasma or hippocampus was analyzed by ELISA. Redox-related protein expression in hippocampus was evaluated by Western blot. Seizure susceptibility was tested by intraperitoneal (i.p.) injection of kainic acid (KA, 10 mg/kg). We found that i.p. infusion of LPS for 7 days induced peripheral inflammation characterized by the increases in plasma levels of interleukin-1β (IL-1β), interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α). This is associated with a significant increase in number of the activated microglia (Iba-1(+) cells), enhanced production of proinflammatory cytokines (including IL-1β, IL-6 and TNF-α), and tissue oxidative stress (upregulations of the NADPH oxidase subunits) in the hippocampus. These cellular and molecular responses to peripheral inflammation were notably blunted by i.c.v. infusion of a cycloxygenase-2 inhibitor, NS398 (5 μg/μl/h). The i.c.v. infusion of tempol (2.5 μg/μl/h), a reactive oxygen species scavenger, protected the hippocampus from oxidative damage with no apparent effect on microglia activation or cytokine production after peripheral inflammation. In the KA-induced seizure model, i.c.v. infusion of both NS398 and tempol ameliorated the increase in seizure susceptibility in animals succumbed to the LPS-induced peripheral inflammation.

CONCLUSIONS:

Together these results indicated that LPS-induced peripheral inflammation evoked neuroinflammation and the subsequent oxidative stress in the hippocampus, resulting in the increase in KA-induced seizure susceptibility. Moreover, protection from neuroinflammation and oxidative stress in the hippocampus exerted beneficial effect on seizure susceptibility following peripheral inflammation.

PMID:
26100815
PMCID:
PMC4477313
DOI:
10.1186/s12929-015-0157-8
[Indexed for MEDLINE]
Free PMC Article

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