Cyclothiazide induces seizure behavior in freely moving rats

Kong, Sue; Qian, Binbin; Liu, Jianhui; Fan, Ming-Xin; Chen, Gong; Wang, Yun

doi:10.1016/j.brainres.2010.07.088

Cited by 22 publications

(31 citation statements)

References 25 publications

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“…Among them, 6 (46.2%) had been observed to have recurrent seizure behavior with the shortest latency of 15 days (mean latency of 76.3 ± 24.8 days) after CTZ injection; 4 of them were without recurrent seizure being observed (Figure 1(a)); and 4 other rats were dead at days 6, 9, 15, and 99 after the CTZ injection (including 1 that had generalized seizure one day before its death at day 15). Recurrent seizure behavior showed as blinking, salivating, facial or automatisms, forelimb clonus, and even rearing and falling, similar to those behaviors showed during the acute phase [12]. Among those 6 rats observed to have recurrent seizure behavior, we found 2 rats having multiple seizure episodes (4 and 3, resp.)…”

Section: Resultssupporting

confidence: 57%

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Downregulated GABA and BDNF-TrkB Pathway in Chronic Cyclothiazide Seizure Model

et al. 2014

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Cyclothiazide (CTZ) has been reported to simultaneously enhance glutamate receptor excitation and inhibit GABAA receptor inhibition, and in turn it evokes epileptiform activities in hippocampal neurons. It has also been shown to acutely induce epileptic seizure behavior in freely moving rats. However, whether CTZ induced seizure rats could develop to have recurrent seizure still remains unknown. In the current study, we demonstrated that 46% of the CTZ induced seizure rats developed to have recurrent seizure behavior as well as epileptic EEG with a starting latency between 2 weeks and several months. In those chronic seizure rats 6 months after the seizure induction by the CTZ, our immunohistochemistry results showed that both GAD and GAT-1 were significantly decreased across CA1, CA3, and dentate gyrus area of the hippocampus studied. In addition, both BDNF and its receptor TrkB were also decreased in hippocampus of the chronic CTZ seizure rats. Our results indicate that CTZ induced seizure is capable of developing to have recurrent seizure, and the decreased GABA synthesis and transport as well as the impaired BDNF-TrkB signaling pathway may contribute to the development of the recurrent seizure. Thus, CTZ seizure rats may provide a novel animal model for epilepsy study and anticonvulsant drug testing in the future.

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Section: Resultssupporting

confidence: 57%

“…CTZ has also been demonstrated to acutely induce seizure behavior and epileptic EEG in freely moving rats [12], which involves extrasynaptic GABAA receptor participation [13]. Thus, CTZ is thought to be a useful convulsant for seizure animal model generation.…”

Section: Introductionmentioning

confidence: 99%

Downregulated GABA and BDNF-TrkB Pathway in Chronic Cyclothiazide Seizure Model

et al. 2014

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“…Using this model, our results demonstrated that extrasynaptic GABA A Rs were downregulated by ~50% Recently, several studies have shown that CTZ is a potent convulsant capable of inducing epileptiform activity both in vivo and in cultured hippocampal neurons [16,17,25] , as well as evoking seizure behavior in freely-moving animals [26] . In the current study, we further extended this epilepsy model to hippocampal slices.…”

Section: Discussionmentioning

confidence: 90%

Activation of extrasynaptic GABAA receptors inhibits cyclothiazide-induced epileptiform activity in hippocampal CA1 neurons

Wan

Liu

et al. 2014

Neurosci. Bull.

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Extrasynaptic GABA(A) receptors (GABA(A)Rs)-mediated tonic inhibition is reported to involve in the pathogenesis of epilepsy. In this study, we used cyclothiazide (CTZ)-induced in vitro brain slice seizure model to explore the effect of selective activation of extrasynaptic GABA(A)Rs by 4,5,6,7-tetrahydroisoxazolo[5,4-c] pyridine-3-ol (THIP) on the CTZ-induced epileptiform activity in hippocampal neurons. Perfusion with CTZ dose-dependently induced multiple epileptiform peaks of evoked population spikes (PSs) in CA1 pyramidal neurons, and treatment with THIP (5 μmol/L) significantly reduced the multiple PS peaks induced by CTZ stimulation. Western blot showed that the δ-subunit of the GABA(A)R, an extrasynaptic specific GABA(A)R subunit, was also significantly down-regulated in the cell membrane 2 h after CTZ treatment. Our results suggest that the CTZ-induced epileptiform activity in hippocampal CA1 neurons is suppressed by the activation of extrasynaptic GABA(A)Rs, and further support the hypothesis that tonic inhibition mediated by extrasynaptic GABA(A)Rs plays a prominent role in seizure generation.

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“…Besides epileptiform activity, we further studied whether THIP can directly modulate CTZ-induced seizure behavior in freely moving rats [38]. CTZ was injected repeatedly each day (0.25 μmol i.c.v.…”

Section: Resultsmentioning

confidence: 99%

“…CTZ induced seizure behavioral test was carried out similarly as previously reported [38]. Briefly, under general anesthetics with sodium pentobarbital (60 mg/kg, i.p.…”

Section: Methodsmentioning

confidence: 99%

Regulation of epileptiform activity by two distinct subtypes of extrasynaptic GABAA receptors

Sun

Kong

et al. 2013

Mol Brain

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BackgroundGABAergic deficit is one of the major mechanisms underlying epileptic seizures. Previous studies have mainly focused on alterations of synaptic GABAergic inhibition during epileptogenesis. Recent work suggested that tonic inhibition may also play a role in regulating epileptogenesis, but the underlying mechanism is not well understood.ResultsWe employed molecular and pharmacological tools to investigate the role of tonic inhibition during epileptogenesis both in vitro and in vivo. We overexpressed two distinct subtypes of extrasynaptic GABAA receptors, α5β3γ2 and α6β3δ receptors, in cultured hippocampal neurons. We demonstrated that overexpression of both α5β3γ2 and α6β3δ receptors enhanced tonic inhibition and reduced epileptiform activity in vitro. We then showed that injection of THIP (5 μM), a selective agonist for extrasynaptic GABAA receptors at low concentration, into rat brain also suppressed epileptiform burst activity and behavioral seizures in vivo. Mechanistically, we discovered that low concentration of THIP had no effect on GABAergic synaptic transmission and did not affect the basal level of action potentials, but significantly inhibited high frequency neuronal activity induced by epileptogenic agents.ConclusionsOur studies suggest that extrasynaptic GABAA receptors play an important role in controlling hyperexcitatory activity, such as that during epileptogenesis, but a less prominent role in modulating a low level of basal activity. We propose that tonic inhibition may play a greater role under pathological conditions than in physiological conditions in terms of modulating neural network activity.

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Cyclothiazide induces seizure behavior in freely moving rats

Cited by 22 publications

References 25 publications

Downregulated GABA and BDNF-TrkB Pathway in Chronic Cyclothiazide Seizure Model

Downregulated GABA and BDNF-TrkB Pathway in Chronic Cyclothiazide Seizure Model

Activation of extrasynaptic GABAA receptors inhibits cyclothiazide-induced epileptiform activity in hippocampal CA1 neurons

Regulation of epileptiform activity by two distinct subtypes of extrasynaptic GABAA receptors

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