Protective effect of the antiepileptic drug candidate talampanel against AMPA-induced striatal neurotoxicity in neonatal rats.

Abstract

2,3-Benzodiazepines represent a family of specific, noncompetitive AMPA receptor antagonists with anticonvulsant and neuroprotective properties. In this study, the antiexcitotoxic potency of the clinical antiepileptic drug candidate, talampanel (4 x 2 mg/kg), and that of two related 2,3-benzodiazepines, 5-(4-aminophenyl)-8-methyl-9H-1,3-dioxolo[4,5-h][2,3]-benzodiazepine (GYKI 52466) (4 x 10 mg/kg) and GYKI 53784 (4 x 2 mg/kg), was investigated in 7-day-old rats. The AMPA antagonists were applied in four consecutive i.p. injections at 1-h intervals, the first dosage was given shortly after the intrastriatal injection of (S)-alpha-amino-3-hydroxy-5,7-methylisoxazole-4-propionic acid (AMPA) (2.5 nmol). All tested compounds protected animals from brain damage induced by AMPA as assessed 5 days later by using a tissue volume determination method based on computer-aided serial section reconstruction. GYKI 53784 (56.1 +/- 5.0% protection) and talampanel (42.5 +/- 5.3% protection) were more potent neuroprotective agents than GYKI 52466 (21.8 +/- 2.8% protection). Furthermore, the three compounds attenuated the unilateral AMPA injection-induced turning behavior and seizure-like events.Our present findings are in agreement with those of other investigators who found talampanel neuroprotective in various in vivo experimental models. These data indicate that besides being a promising antiepileptic drug candidate talampanel may have a value in the pharmacotherapy of acute and chronic neurodegenerative diseases, including perinatal ischemia/hypoxia-induced brain injuries, as well.

• Authors: Ildikó Világi, József Takács, Attila Gulyás-Kovács, Ilona Banczerowski-Pelyhe, István Tarnawa
• Journal: Brain research bulletin (Brain Res Bull) Vol. 59 Issue 1 Pg. 35-40 (Oct 15 2002) ISSN: 0361-9230 [Print] United States
• PMID: 12372546 (Publication Type: Journal Article)
• Copyright: Copyright 2002 Elsevier Science Inc.

Chemical References

• Anti-Anxiety Agents
• Excitatory Amino Acid Antagonists
• Neuroprotective Agents
• Neurotoxins
• Receptors, AMPA
• GYKI 52466
• Benzodiazepines
• Glutamic Acid
• alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid
• talampanel

Topics

• Animals
• Animals, Newborn
• Anti-Anxiety Agents (pharmacology)
• Asphyxia Neonatorum (drug therapy, metabolism, physiopathology)
• Behavior, Animal (drug effects, physiology)
• Benzodiazepines (pharmacology)
• Cell Death (drug effects, physiology)
• Epilepsy (drug therapy, metabolism, physiopathology)
• Excitatory Amino Acid Antagonists (pharmacology)
• Female
• Glutamic Acid (metabolism)
• Humans
• Hypoxia-Ischemia, Brain (drug therapy, metabolism, physiopathology)
• Infant, Newborn
• Male
• Movement Disorders (drug therapy, physiopathology)
• Neostriatum (drug effects, metabolism, physiopathology)
• Neuroprotective Agents (pharmacology)
• Neurotoxins (metabolism)
• Rats
• Receptors, AMPA (agonists, antagonists & inhibitors, metabolism)
• Synaptic Transmission (drug effects, physiology)
• alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid (toxicity)