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

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.

Monoaminergic Mechanisms in Epilepsy May Offer Innovative Therapeutic Opportunity for Monoaminergic Multi-Target Drugs

“…Despite all these initial negative results, recent interest in the 5-HT 3 R subtype emerged in the PTZ model for generalized seizures and in PTZ kindling. Indeed, 5-HT 3 R agonism exhibited dose-dependent anticonvulsant effects in the PTZ model (Li et al, 2014). Moreover, the 5-HT 3 R subtype seems to play a prominent role in mediating the anticonvulsant effects of various selective 5-HT reuptake inhibitors in this classical PTZ model for generalized epilepsy (Payandemehr et al, 2012; Alhaj et al, 2015).…”

Chemogenetic Inactivation of Dorsal Anterior Cingulate Cortex Neurons Disrupts Attentional Behavior in Mouse

“…As previous reports suggest that high baseline c-fos activation is required to detect the reduced c-fos activation by CNO (Koch et al, 2015;Sasaki et al, 2011), we elevated the baseline c-fos activation with PTZ (65 mg/kg), a GABA A receptor antagonist (Andre et al, 1998;Li et al, 2014), to allow for in vivo quantification. We found that CNO (10 mg/kg) significantly decreased the percentage of total hM4Di-expressed cells that coexpress c-fos in both hSyn-and CaMKII-hM4Di mice injected with PTZ (Supplementary Figure S2).…”

Ectopic Expression of α6 and δ GABAAReceptor Subunits in Hilar Somatostatin Neurons Increases Tonic Inhibition and Alters Network Activity in the Dentate Gyrus

“…Fos labeling was used to identify neurons that were strongly activated, as described previously in response to PTZ administration (Li et al, 2014) and spontaneous seizures (Peng and Houser, 2005). In preliminary studies, Fos labeling was evaluated in SOM-Cre mice with no transfections (n ϭ 4).…”