Inhibition of the betaine-GABA transporter (mGAT2/BGT-1) modulates spontaneous electrographic bursting in the medial entorhinal cortex (mEC)

• Published in: Epilepsy research 2008-03, Vol.79 (1), p.6-13
• Main Authors: Smith, Misty D, Saunders, Gerald W, Clausen, Rasmus P, Frǿlund, Bente, Krogsgaard-Larsen, Povl, Larsson, Orla M, Schousboe, Arne, Wilcox, Karen S, White, H. Steve
• Format: Article
• Language: English
• Subjects: Animals; Biological and medical sciences; Carrier Proteins - antagonists & inhibitors; Carrier Proteins - metabolism; Combined mEC–HC slices; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Interactions; EF1502; Electric Stimulation - methods; Entorhinal Cortex - drug effects; Entorhinal Cortex - physiopathology; Entorhinal Cortex - radiation effects; Evoked Potentials - drug effects; Evoked Potentials - physiology; Evoked Potentials - radiation effects; GABA Agonists - pharmacology; Glia; Headache. Facial pains. Syncopes. Epilepsia. Intracranial hypertension. Brain oedema. Cerebral palsy; In Vitro Techniques; Investigative techniques, diagnostic techniques (general aspects); Isoxazoles - pharmacology; Kainic Acid; Male; Medical sciences; Nervous system; Nervous system (semeiology, syndromes); Neurology; Nipecotic Acids - pharmacology; Radiodiagnosis. Nmr imagery. Nmr spectrometry; Rats; Rats, Sprague-Dawley; Status Epilepticus - chemically induced; Status Epilepticus - pathology; Tiagabine
• ISSN: 0920-1211; 1872-6844
• DOI: 10.1016/j.eplepsyres.2007.12.009

Summary Disruptions in GABAergic neurotransmission have been implicated in numerous CNS disorders, including epilepsy and neuropathic pain. Selective inhibition of neuronal and glial GABA transporter subtypes may offer unique therapeutic options for regaining balance between inhibitory and excitatory systems. The ability of two GABA transport inhibitors to modulate inhibitory tone via inhibition of mGAT1 (tiagabine) or mGAT2/BGT-1 ( N -[4,4-bis(3-methyl-2-thienyl)-3-butenyl]-4-(methylamino-4,5,6,7-tetrahydrobenzo[ d ]isoxazol-3-ol), also known as EF1502) was evaluated using an in vitro model of spontaneous interictal-like bursting (SB). SBs were recorded extracellularly in combined mEC–HC horizontal brain slices (400 μm; 31 ± 1 °C) obtained from KA-treated rats. Slice recordings demonstrated that EF1502 exhibited a concentration-dependent reduction in SB frequency. EF1502 significantly reduced SB rate to 32% of control at the 30 μM concentration, while reducing the area and duration of SB activity to 60% and 46% of control, respectively, at the 10 μM concentration. In contrast, the GAT1 selective inhibitor tiagabine (3, 10, and 30 μM) was unable to significantly reduce the frequency of SB activity in the mEC, despite significantly reducing both the duration (51% of control) and area (58% of control) of the SB at concentrations as low as 3 μM. The ability of EF1502, but not tiagabine, to inhibit SBs in the mEC suggests that this in vitro model of pharmacoresistant SB activity is useful to differentiate between novel anticonvulsants with similar mechanisms of action and suggests a therapeutic potential for non-GAT1 transport inhibitors.