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

Wan, Li; Liu, Xu; Wu, Zheng; Ren, Wanting; Kong, Sue; Dargham, Raya Abou; Cheng, Longzhen; Wang, Yun

doi:10.1007/s12264-014-1466-8

Cited by 13 publications

(10 citation statements)

References 51 publications

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“…Also, the anesthetic 4,5,6,7-tetrahydroisoxazolo(5,4-c)pyridin-3-ol (THIP, gaboxadol) agonizes the δ subunit. THIP can reduce spikes in vitro and in vivo [ 125 , 126 ]. In a clinical study with a small sample size, a trend toward seizure reduction was demonstrated [ 127 ].…”

Section: Toward Antiepileptic Drugs That Target Tonic Gaba Signalingmentioning

confidence: 99%

Tonic GABAA Receptors as Potential Target for the Treatment of Temporal Lobe Epilepsy

et al. 2015

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Tonic GABAA receptors are a subpopulation of receptors that generate long-lasting inhibition and thereby control network excitability. In recent years, these receptors have been implicated in various neurological and psychiatric disorders, including Parkinson’s disease, schizophrenia, and epilepsy. Their distinct subunit composition and function, compared to phasic GABAA receptors, opens the possibility to specifically modulate network properties. In this review, the role of tonic GABAA receptors in epilepsy and as potential antiepileptic target will be discussed.

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Section: Toward Antiepileptic Drugs That Target Tonic Gaba Signalingmentioning

confidence: 99%

Tonic GABAA Receptors as Potential Target for the Treatment of Temporal Lobe Epilepsy

et al. 2015

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“…Acute perfusion with 50 lmol/L resveratrol reduced the bicuculline-evoked epileptiform activity in the CA1 region. Similarly, Wan et al demonstrated that cyclothiazide-induced epileptiform activity in CA1 neurons is suppressed by the activation of extrasynaptic GABA A Rs [29]. Together, these results further suggest that the GABA A R plays a prominent role in seizure generation, and resveratrol inhibits the electrical activity of hippocampal pyramidal neurons by enhancing GABAergic synaptic inhibition.…”

Section: Discussionmentioning

confidence: 66%

Protective Effect of Resveratrol on the Brain in a Rat Model of Epilepsy

You

et al. 2017

Neurosci. Bull.

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Accumulating evidence has suggested resveratrol as a promising drug candidate for the treatment of epilepsy. To validate this, we tested the protective effect of resveratrol on a kainic acid (KA)-induced epilepsy model in rats and investigated the underlying mechanism. We found that acute resveratrol application partially inhibited evoked epileptiform discharges in the hippocampal CA1 region. During acute, silent and chronic phases of epilepsy, the expression of hippocampal kainate glutamate receptor (GluK2) and the GABA receptor alpha1 subunit (GABAR-alpha1) was up-regulated and down-regulated, respectively. Resveratrol reversed these effects and induced an antiepileptic effect. Furthermore, in the chronic phase, resveratrol treatment inhibited the KA-induced increased glutamate/GABA ratio in the hippocampus. The antiepileptic effects of resveratrol may be partially attributed to the reduction of glutamate-induced excitotoxicity and the enhancement in GABAergic inhibition.

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“…CTZ not only blocks AMPA receptor desensitization, but also inhibits GABAA receptors [ 8 ], and GABAA receptors were involved in the CTZ induced epileptiform activities in hippocampal neurons [ 9 – 11 , 13 ]. In this study, we reported further that, at the chronic phase of the CTZ seizure rat, there was a significant reduction of the GAD and GAT containing neurons in the hippocampus.…”

Section: Discussionmentioning

confidence: 99%

“…Cyclothiazide (CTZ) not only blocks AMPA receptor desensitization, but also inhibits GABAA receptors [ 8 ], which leads to induction of epileptiform activities in hippocampal neurons in both in vitro and in vivo preparations [ 7 , 9 – 11 ]. 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 ].…”

Section: Introductionmentioning

confidence: 99%

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

Cited by 13 publications

References 51 publications

Tonic GABAA Receptors as Potential Target for the Treatment of Temporal Lobe Epilepsy

Tonic GABAA Receptors as Potential Target for the Treatment of Temporal Lobe Epilepsy

Protective Effect of Resveratrol on the Brain in a Rat Model of Epilepsy

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

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