title: Anticonvulsant characteristics of pyridoxyl-gamma-aminobutyrate, PL-GABA.
abstract: GABA is the major inhibitory neurotransmitter in the central nervous system, and its concentration in the brain in associated with a variety of neurological disorders, including seizures, convulsions, and epilepsy. The concentration of GABA is modulated by the pyridoxal-5'-phosphate (PLP)-dependent enzymes, GAD and GABA-T. In this study, we generated pyridoxyl-gamma-aminobutyrate (PL-GABA), a novel GABA analogue composed of pyridoxyl and GABA, and have also characterized its anticonvulsant and pharmacological functions in vitro. The results of biodistribution studies revealed that PL-GABA is capable of crossing the blood-brain barrier. PL-GABA evidenced anticonvulsant activity in a wide range of epilepsy models, some of which were electrically-based (MES seizures) and some chemically-based (bicuculline, pentylenetetrazol (PTZ), picrotoxine, 3-mercaptopropionic acid). Following a timed subcutaneous administration of PTZ to mice, PL-GABA consistently increased the latencies to first twitch and clonus. In addition, PL-GABA displayed no signs of tolerance after subchronic (10 day) treatment. PL-GABA appears to exert its anticonvulsant effects by influencing seizure spread and by raising the seizure threshold. Therefore, our results indicate that PL-GABA exerts a broad-spectrum anticonvulsant effect, and identify the potential for reduced PL-GABA tolerance as an additional positive profile for novel antiepileptic drugs.
authors.affiliation: Department of Anatomy, College of Medicine, Hallym University, Chunchon 200-702, Korea.
authors.forename: Tae-Cheon
authors.initials: TC
authors.lastname: Kang
authors.forename: Jeong Han
authors.initials: JH
authors.lastname: Kang
authors.forename: Hyun Tae
authors.initials: HT
authors.lastname: Kim
authors.forename: Su Jin
authors.initials: SJ
authors.lastname: Lee
authors.forename: Ung-Kyu
authors.initials: UK
authors.lastname: Choi
authors.forename: Ji-Eun
authors.initials: JE
authors.lastname: Kim
authors.forename: Sung-Eun
authors.initials: SE
authors.lastname: Kwak
authors.forename: Dae-Won
authors.initials: DW
authors.lastname: Kim
authors.forename: Soo Young
authors.initials: SY
authors.lastname: Choi
authors.forename: Oh-Shin
authors.initials: OS
authors.lastname: Kwon
mesh_terms: D015097:3-Mercaptopropionic Acid; D000818:Animals; D000927:Anticonvulsants / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000633:toxicity; D001640:Bicuculline; D004361:Drug Tolerance; D004594:Electrophysiology; D004597:Electroshock; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004827:Epilepsy / Q000235:genetics / Q000517:prevention & control; D005849:Gerbillinae; D008274:Magnesium / Q000502:physiology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D020258:Neurotoxicity Syndromes / Q000503:physiopathology / Q000523:psychology; D010433:Pentylenetetrazole; D010852:Picrotoxin; D011732:Pyridoxal Phosphate / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology / Q000633:toxicity; D051381:Rats; D017207:Rats, Sprague-Dawley; D012640:Seizures / Q000139:chemically induced / Q000235:genetics / Q000517:prevention & control; D014018:Tissue Distribution; D005680:gamma-Aminobutyric Acid / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology / Q000633:toxicity
chemical_list: D015097:3-Mercaptopropionic Acid; D000927:Anticonvulsants; D001640:Bicuculline; D004791:Enzyme Inhibitors; D008274:Magnesium; D010433:Pentylenetetrazole; D010852:Picrotoxin; D011732:Pyridoxal Phosphate; D005680:gamma-Aminobutyric Acid; C059414:pyridoxal phosphate gamma-aminobutyric acid