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: Tae-Cheon Kang, Jeong Han Kang, Hyun Tae Kim, Su Jin Lee, Ung-Kyu Choi, Ji-Eun Kim, Sung-Eun Kwak, Dae-Won Kim, Soo Young Choi, Oh-Shin Kwon
• Journal: Neuropharmacology (Neuropharmacology) Vol. 54 Issue 6 Pg. 954-64 (May 2008) ISSN: 0028-3908 [Print] England
• PMID: 18346762 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Anticonvulsants
• Enzyme Inhibitors
• Picrotoxin
• gamma-Aminobutyric Acid
• Pyridoxal Phosphate
• pyridoxal phosphate gamma-aminobutyric acid
• 3-Mercaptopropionic Acid
• Magnesium
• Pentylenetetrazole
• Bicuculline

Topics

• 3-Mercaptopropionic Acid
• Animals
• Anticonvulsants (pharmacokinetics, pharmacology, toxicity)
• Bicuculline
• Drug Tolerance
• Electrophysiology
• Electroshock
• Enzyme Inhibitors (pharmacology)
• Epilepsy (genetics, prevention & control)
• Gerbillinae
• Magnesium (physiology)
• Male
• Mice
• Mice, Inbred BALB C
• Neurotoxicity Syndromes (physiopathology, psychology)
• Pentylenetetrazole
• Picrotoxin
• Pyridoxal Phosphate (analogs & derivatives, pharmacokinetics, pharmacology, toxicity)
• Rats
• Rats, Sprague-Dawley
• Seizures (chemically induced, genetics, prevention & control)
• Tissue Distribution
• gamma-Aminobutyric Acid (analogs & derivatives, pharmacokinetics, pharmacology, toxicity)