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. 2014 Apr 1;9(4):e93158.
doi: 10.1371/journal.pone.0093158. eCollection 2014.

The Anticonvulsant Effects of SR 57227 on Pentylenetetrazole-Induced Seizure in Mice

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Free PMC article

The Anticonvulsant Effects of SR 57227 on Pentylenetetrazole-Induced Seizure in Mice

Bingjin Li et al. PLoS One. .
Free PMC article

Abstract

Recently, studies have shown that serotonin plays an important role in the control of seizure. However, the specific role of 5-HT receptor subtypes is not yet well described, in particular that of the 5-HT3 receptor. The present study was aimed to investigate the role of 5-HT3 receptor on the pentylenetetrazole (PTZ)-induced seizure in mice. Firstly, seizure latency was significantly prolonged by a 5-HT3 receptor agonist SR 57227 in a dose-dependent manner. Seizure score and mortality were also decreased by SR 57227 in PTZ-treated mice. Furthermore, these anticonvulsant effects of SR 57227 were inhibited by a 5-HT3 receptor antagonist ondansetron. However, ondansetron alone had no effect on seizure latency, seizure score or mortality at different doses. Immunohistochemical studies have also shown that c-Fos expression was significantly increased in hippocampus (dentate gyrus, CA1, CA3 and CA4) of PTZ-treated mice. Furthermore, c-Fos expression was significantly inhibited by ondansetron in mice treated with PTZ and SR 57227. An ELISA study showed that SR 57227 attenuated the PTZ-induced inhibitory effects of GABA levels in hippocampus and cortex, and the attenuated effects of SR 57227 were antagonized by ondansetron in hippocampus but not cortex. Our findings suggest that activation of 5-HT3 receptor by SR 57227, which plays an important role on the control of seizure induced by PTZ, may be related to GABA activity in hippocampus. Therefore, 5-HT3 receptor subtype is a potential target for the treatment of epilepsy.

Conflict of interest statement

Competing Interests: The authors have declared that no competing interests exist.

Figures

Figure 1
Figure 1. Effects of SR 57227 and ondansetron on seizure latency in PTZ-treated mice.
PTZ: pentylenetetrazole (65 mg/kg, i.p.); SR 57227: 1, 5 and 10 mg/kg, i.p.; Ond: ondansetron (0.2, 0.5 and 1 mg/kg, i.p.); VPA: sodium valproate (400 mg/kg, p.o.). Columns represent the mean ± S.E.M. n  =  8–10. ** P<0.01 vs saline group.
Figure 2
Figure 2. Effects of ondansetron on SR 57227-induced prolonged seizure latency.
PTZ: pentylenetetrazole (65 mg/kg, i.p.); SR 57227: 10 mg/kg, i.p; Ond: ondansetron (0.2 mg/kg, i.p.); VPA: sodium valproate (400 mg/kg, p.o.). Columns represent the mean ± S.E.M. n  =  8–10. ** P<0.01 vs PTZ group.
Figure 3
Figure 3. Effects of ondansetron and SR 57227 on c-Fos expression in hippocampus.
PTZ: pentylenetetrazole (65 mg/kg, i.p.); SR 57227: 10 mg/kg, i.p; Ond: ondansetron (0.2 mg/kg, i.p.); VPA: sodium valproate (400 mg/kg, p.o.). DG: dentate gyrus; Columns represent the mean ± S.E.M. n  =  6–7. ### P<0.001 vs control group; ** P<0.01, *** P<0.001 vs PTZ group.
Figure 4
Figure 4. Effects of SR 57227 on GABA levels, normalized to control group, in hippocampus and cortex.
PTZ: pentylenetetrazole (65 mg/kg, i.p.); SR 57227: 10 mg/kg, i.p; Ond: ondansetron (0.2 mg/kg, i.p.); VPA: sodium valproate (400 mg/kg, p.o.). Values are expressed as mean + SEM. n  =  7–10. * P<0.05 vs saline group; # P<0.05 vs PTZ group.

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Grant support

This work was supported by Natural Science Foundation of China (31171123; 31300850; 81328011). The project was supported by Program for New Century Excellent Talents in University (NCET-13-0715); Jilin Provincial Department of Human Resources and Social Security Project ([2012]39); and Jilin Science and Technology Agency funding (20110726; 20140414039GH; 20130303095YY). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
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