BDNF-TrkB signaling pathway mediates the induction of epileptiform activity induced by a convulsant drug cyclothiazide.
Brain-derived neurotrophic factor (BDNF) and its receptor TrkB play an important function in neuronal development and synaptic plasticity. Recently we have established that cyclothiazide (CTZ) is a novel convulsant drug inducing robust epileptiform activity in hippocampal neurons both in vitro and in vivo. However, the molecular mechanisms underlying such convulsant action of CTZ are unknown. Here, we investigated potential roles of BDNF-TrkB signaling pathway in the CTZ-induction of epileptiform activity. In anaesthetized rats, CTZ dose-dependently induced epileptiform activity characterized by progressing of multiple peaks of population spikes, spontaneous spiking events, and synchronized epileptiform bursts. Pre-injection of a receptor tyrosine kinase inhibitor K252a or a specific antibody for TrkB receptors before intracerebroventricular injection of CTZ significantly suppressed the epileptiform activity induced by CTZ. Similarly, in cultured hippocampal pyramidal neurons, pre-treatment with CTZ together with K252a or TrkB-receptor antibody also inhibited the CTZ-induction of epileptiform activity. Furthermore, we demonstrated that acute application of K252a in hippocampal cultures inhibited epileptiform bursts and action potential firing. We conclude that activation of BDNF-TrkB signaling pathway is fundamentally important during the CTZ-induction of epileptiform activity both in vitro and in vivo.
Wang
Yun
Y
Institutes of Brain Science and State Key Laboratory for Medical Neurobiology, Fudan University, Shanghai 200032, China. yunwang@fudan.edu.cn
Qi
Jin-Shun
JS
Kong
Shuzhen
S
Sun
Yajie
Y
Fan
Jing
J
Jiang
Min
M
Chen
Gong
G
D000200:Action Potentials / Q000187:drug effects; D000704:Analysis of Variance; D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D000959:Antihypertensive Agents / Q000494:pharmacology*; D001581:Benzothiadiazines / Q000494:pharmacology*; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism*; D002227:Carbazoles / Q000494:pharmacology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004827:Epilepsy / Q000139:chemically induced* / Q000473:pathology / Q000503:physiopathology*; D006624:Hippocampus / Q000473:pathology; D066298:In Vitro Techniques; D026121:Indole Alkaloids / Q000494:pharmacology; D008297:Male; D009474:Neurons / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D020813:Receptor, trkB / Q000276:immunology / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects* / Q000502:physiology; D013997:Time Factors
D000906:Antibodies; D000959:Antihypertensive Agents; D001581:Benzothiadiazines; D019208:Brain-Derived Neurotrophic Factor; D002227:Carbazoles; D004791:Enzyme Inhibitors; D026121:Indole Alkaloids; C049985:staurosporine aglycone; D020813:Receptor, trkB; C004639:cyclothiazide