Effect of diazoxide on regulation of vesicular and plasma membrane GABA transporter genes and proteins in hippocampus of rats subjected to picrotoxin-induced kindling.
Epileptiform discharges and behavioral seizures may be the consequences of excess excitation from inadequate inhibitory effects associated with gamma-aminobutyric acid (GABA). GABA is taken up and accumulated in synaptic vesicles by the action of vesicular GABA transporter (VGAT) before its release into the synaptic cleft, and removed from synaptic regions by the action of transporter proteins GABA transporter-1 (GAT-1) and GABA transporter-3 (GAT-3). In this experiment, the effects of diazoxide (DIZ) on the VGAT, GAT-1 and GAT-3 mRNA and protein levels in hippocampus, and on the seizure activities of picrotoxin (PTX)-induced kindling rats were observed. DIZ caused increase in the quantity of VGAT mRNAs and proteins, and down regulation of GABA transporters GAT-1 and GAT-3 mRNAs and proteins after the PTX re-kindling. Furthermore, DIZ produced not only a prompt but also a later suppression of PTX-induced seizures. Although DIZ has effects on ATP-sensitive potassium (K(ATP)) channels when measured in vitro, our study suggests that additional mechanisms of action may involve the regulation of GABA transporters, which may aid in understanding epileptogenesis and inform investigators about future design and development of K(ATP) channel openers to treat epilepsy.
Jiang
Ke-Wen
KW
Department of Neurology, Children's Hospital School of Medicine, Zhejiang University, 57 Zhugan Xiang, Hangzhou 310003, China. jiangkewen@21cn.com
Gao
Feng
F
Shui
Quan-Xiang
QX
Yu
Zhong-Sheng
ZS
Xia
Zhe-Zhi
ZZ
D000818:Animals; D002462:Cell Membrane / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D003981:Diazoxide / Q000494:pharmacology*; D006624:Hippocampus / Q000187:drug effects* / Q000378:metabolism; D007696:Kindling, Neurologic / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D026901:Membrane Transport Proteins / Q000096:biosynthesis* / Q000235:genetics; D010852:Picrotoxin / Q000633:toxicity; D051381:Rats; D017207:Rats, Sprague-Dawley; D050495:Vesicular Inhibitory Amino Acid Transport Proteins
D003981:Diazoxide; D026901:Membrane Transport Proteins; D010852:Picrotoxin; D050495:Vesicular Inhibitory Amino Acid Transport Proteins; C493406:vesicular GABA transporter