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

Abstract

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.

Topiramate protects against glutamate excitotoxicity via activating BDNF/TrkB-dependent ERK pathway in rodent hippocampal neurons

“…Previous investigations illustrated that suppressions of BDNF expression in animal models of ischemia (Larsson et al, 1999) and epilepsy (Kong et al, 2014) were found to result in marked cellular damage while overexpression via intraventricular injection of BDNF was reported to significantly have protection against vulnerable cells in the hippocampal CA1 subfield following global ischemia (Beck et al, 1994). Results from our current work depicted that TPM evidently prevented the reduction of BDNF in cultured hippocamal neurons subjected to glutamate lesion.…”

Protective Role of L-3-n-Butylphthalide in Cognitive Function and Dysthymic Disorders in Mouse With Chronic Epilepsy

“…Treatment with antidepressant or antianxiety drugs can restore Bdnf mRNA level in stress-induced model ( Smith et al, 1995 ; Kozisek et al, 2008 ). Although it has been reported that BDNF expression was enhanced in pilocarpine-induced SE ( Thomas et al, 2016 ), BDNF has also been found decreased in patients with chronic temporal lobe epilepsy (TLE) and in animal model of chronic cyclothiazide seizure ( Kong and Cheng, 2014 ; Chen et al, 2016 ). Besides, Xiang et al (2014) pointed out that NBP alleviated cognitive dysfunction in APP mice by BDNF/TrkB/PI3K/AKT pathway.…”

In vivo effects of bumetanide at brain concentrations incompatible with NKCC1 inhibition on newborn DGC structure and spontaneous EEG seizures following hypoxia-induced neonatal seizures

“…Six slides for each rat were made and rinsed in 1% toluidin blue solution for 20 min at 56°C, rinsed quickly in distilled water, differentiated in 95% alcohol for 2-5 min, dehydrated in alcohol of different concentration for 5 min at each concentration, cleared in xylene for 5 min, and then mounted with neutral gum solution (Kong et al, 2014). Slices were observed under a microscope at Â40 magnification.…”