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

Ho YH, Lin YT, Wu CW, Chao YM, Chang AY, Chan JY - J. Biomed. Sci. (2015)

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Biological Sciences, National Sun Yat-sen University, Kaohsiung, 804, Taiwan. yhho@vghks.gov.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.

No MeSH data available.


Related in: MedlinePlus

The COX-2-dependent upregulations of the NADPH oxidase subunits in the hippocampus after intraperitoneal LPS infusion. Representative gels (insert) and densitometric analysis of results from Western blot showing changes in expression of gp91phox (a), p47phox (b) and p67phox (c) in the hippocampus, measured on day 7 after intraperitoneal infusion via an osmotic minipump of saline or LPS (2.5 mg/kg/day) for 7 days alone or with additional intracerebroventricular infusion of NS398 (5 μg/μl/h, dissolved in 1 % DMSO), tempol (2.5 μg/μl/h, dissolved in saline) or the corresponding vehicle. Values are mean ± SEM, n = 8–10 rats per group. *P <0.05 vs. saline-treated group; #P <0.05 vs. LPS-treated group in the post hoc Scheffé multiple-range test
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Fig4: The COX-2-dependent upregulations of the NADPH oxidase subunits in the hippocampus after intraperitoneal LPS infusion. Representative gels (insert) and densitometric analysis of results from Western blot showing changes in expression of gp91phox (a), p47phox (b) and p67phox (c) in the hippocampus, measured on day 7 after intraperitoneal infusion via an osmotic minipump of saline or LPS (2.5 mg/kg/day) for 7 days alone or with additional intracerebroventricular infusion of NS398 (5 μg/μl/h, dissolved in 1 % DMSO), tempol (2.5 μg/μl/h, dissolved in saline) or the corresponding vehicle. Values are mean ± SEM, n = 8–10 rats per group. *P <0.05 vs. saline-treated group; #P <0.05 vs. LPS-treated group in the post hoc Scheffé multiple-range test

Mentions: Accumulation of ROS in the hippocampus indicates an imbalance in tissue redox homeostasis. At the end of 7-day peripheral LPS infusion, protein expressions of the gp91phox and p67phox, but not p47phox, subunits of the NADPH oxidase in the hippocampus were significantly increased (Fig. 4). At the same time, protein expression of antioxidants, including Cu/Zn SOD, MnSOD, catalase and GPx, were also increased in the hippocampus (Fig. 5). All these molecular events induced by peripheral LPS infusion were notably attenuated by i.c.v. infusion of NS398 (5 μg/μl/h) or tempol (2.5 μg/μl/h) for 7 days. Protein expression of p22phox subunit in the hippocampus was under our detection limit; and was not affected by peripheral LPS infusion alone or with additional i.c.v. infusion of the inhibitors (data not shown).Fig. 4


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

Ho YH, Lin YT, Wu CW, Chao YM, Chang AY, Chan JY - J. Biomed. Sci. (2015)

The COX-2-dependent upregulations of the NADPH oxidase subunits in the hippocampus after intraperitoneal LPS infusion. Representative gels (insert) and densitometric analysis of results from Western blot showing changes in expression of gp91phox (a), p47phox (b) and p67phox (c) in the hippocampus, measured on day 7 after intraperitoneal infusion via an osmotic minipump of saline or LPS (2.5 mg/kg/day) for 7 days alone or with additional intracerebroventricular infusion of NS398 (5 μg/μl/h, dissolved in 1 % DMSO), tempol (2.5 μg/μl/h, dissolved in saline) or the corresponding vehicle. Values are mean ± SEM, n = 8–10 rats per group. *P <0.05 vs. saline-treated group; #P <0.05 vs. LPS-treated group in the post hoc Scheffé multiple-range test
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4477313&req=5

Fig4: The COX-2-dependent upregulations of the NADPH oxidase subunits in the hippocampus after intraperitoneal LPS infusion. Representative gels (insert) and densitometric analysis of results from Western blot showing changes in expression of gp91phox (a), p47phox (b) and p67phox (c) in the hippocampus, measured on day 7 after intraperitoneal infusion via an osmotic minipump of saline or LPS (2.5 mg/kg/day) for 7 days alone or with additional intracerebroventricular infusion of NS398 (5 μg/μl/h, dissolved in 1 % DMSO), tempol (2.5 μg/μl/h, dissolved in saline) or the corresponding vehicle. Values are mean ± SEM, n = 8–10 rats per group. *P <0.05 vs. saline-treated group; #P <0.05 vs. LPS-treated group in the post hoc Scheffé multiple-range test
Mentions: Accumulation of ROS in the hippocampus indicates an imbalance in tissue redox homeostasis. At the end of 7-day peripheral LPS infusion, protein expressions of the gp91phox and p67phox, but not p47phox, subunits of the NADPH oxidase in the hippocampus were significantly increased (Fig. 4). At the same time, protein expression of antioxidants, including Cu/Zn SOD, MnSOD, catalase and GPx, were also increased in the hippocampus (Fig. 5). All these molecular events induced by peripheral LPS infusion were notably attenuated by i.c.v. infusion of NS398 (5 μg/μl/h) or tempol (2.5 μg/μl/h) for 7 days. Protein expression of p22phox subunit in the hippocampus was under our detection limit; and was not affected by peripheral LPS infusion alone or with additional i.c.v. infusion of the inhibitors (data not shown).Fig. 4

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Biological Sciences, National Sun Yat-sen University, Kaohsiung, 804, Taiwan. yhho@vghks.gov.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.

No MeSH data available.


Related in: MedlinePlus