Neuroprotective and anticonvulsant effects of EGIS-8332, a non-competitive AMPA receptor antagonist, in a range of animal models.

Abstract

BACKGROUND AND PURPOSE:

Blockade of AMPA (alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) receptors is a good treatment option for a variety of central nervous system disorders. The present study evaluated the neuroprotective and anticonvulsant effects of EGIS-8332, a non-competitive AMPA receptor antagonist, as a potential drug candidate.

EXPERIMENTAL APPROACH:

AMPA antagonist effects of EGIS-8332 were measured using patch-clamp techniques. Neuroprotective and anticonvulsant effects of EGIS-8332 were evaluated in various experimental models, relative to those of GYKI 53405.

KEY RESULTS:

EGIS-8332 inhibited AMPA currents in rat cerebellar Purkinje cells and inhibited the AMPA- and quisqualate-induced excitotoxicity in primary cultures of telencephalon neurons (IC(50)=5.1-9.0 microM), in vitro. Good anticonvulsant actions were obtained in maximal electroshock-, sound- and chemically-induced seizures (range of ED(50)=1.4-14.0 mg kg(-1) i.p.) in mice. Four days after transient global cerebral ischaemia, EGIS-8332 decreased neuronal loss in the hippocampal CA1 area in gerbils and rats. EGIS-8332 dose-dependently reduced cerebral infarct size after permanent middle cerebral artery occlusion in mice and rats (minimum effective dose=3 mg kg(-1) i.p.). Side effects of EGIS-8332 emerged much above its pharmacologically active doses. A tendency for better efficacy of GYKI 53405 than that of EGIS-8332 was observed in anticonvulsant tests that reached statistical significance in few cases, while the contrary was perceived in cerebral ischaemia tests.

CONCLUSIONS AND IMPLICATIONS:

EGIS-8332 seems suitable for further development for the treatment of epilepsy, ischaemia and stroke based on its efficacy in a variety of experimental disease models, and on its low side effect potential.

• Authors: G Gigler, K Móricz, M Agoston, A Simó, M Albert, A Benedek, G Kapus, S Kertész, M Vegh, J Barkóczy, B Markó, G Szabó, E Matucz, I Gacsályi, G Lévay, L G Hársing Jr, G Szénási
• Journal: British journal of pharmacology (Br J Pharmacol) Vol. 152 Issue 1 Pg. 151-60 (Sep 2007) ISSN: 0007-1188 [Print] England
• PMID: 17603549 (Publication Type: Comparative Study, Journal Article)

Chemical References

• Anticonvulsants
• EGIS-8332
• Excitatory Amino Acid Agonists
• Neuroprotective Agents
• Receptors, AMPA
• Benzodiazepines
• alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid
• Quisqualic Acid
• talampanel

Topics

• Animals
• Anticonvulsants (adverse effects, pharmacokinetics, pharmacology, therapeutic use)
• Benzodiazepines (metabolism, pharmacology, therapeutic use)
• Brain (drug effects, metabolism, pathology)
• Brain Ischemia (metabolism, pathology, prevention & control)
• Cells, Cultured
• Disease Models, Animal
• Dose-Response Relationship, Drug
• Excitatory Amino Acid Agonists (toxicity)
• Gerbillinae
• Male
• Membrane Potentials (drug effects)
• Mice
• Mice, Inbred DBA
• Neurons (drug effects, metabolism)
• Neuroprotective Agents (adverse effects, pharmacokinetics, pharmacology, therapeutic use)
• Patch-Clamp Techniques
• Purkinje Cells (drug effects, metabolism)
• Quisqualic Acid (toxicity)
• Rats
• Rats, Sprague-Dawley
• Rats, Wistar
• Receptors, AMPA (antagonists & inhibitors, metabolism)
• Seizures (etiology, metabolism, prevention & control)
• Telencephalon (drug effects, metabolism)
• Time Factors
• alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid (metabolism)