Research Paper
Subject Category: Neuropharmacology
British Journal of Pharmacology (2007) 152, 151–160; doi:10.1038/sj.bjp.0707362; published online 2 July 2007
Neuroprotective and anticonvulsant effects of EGIS-8332, a non-competitive AMPA receptor antagonist, in a range of animal models
G Gigler1, K Móricz1, M ágoston1, A Simó1, M Albert1, A Benedek1, G Kapus1, S Kertész1, M Vegh1, J Barkóczy1, B Markó1, G Szabó1, É Matucz1,2, I Gacsályi1, G Lévay1, L G Hársing Jr1 and G Szénási1
1Division of Preclinical Research, EGIS Pharmaceuticals PLC, Budapest, Hungary
Correspondence: Dr G Szénási, Pharmacology Laboratory I, EGIS Pharmaceuticals PLC, Bokenyfoldi ut 116, Budapest 10, PO Box 100, Budapest H-1475, Hungary. E-mail: szenasi.gabor@egis.hu
2Current address: National Institute of Pharmacy, H-1051 Budapest, Zrinyi u 3, Hungary.
Received 13 February 2007; Revised 12 April 2007; Accepted 30 May 2007; Published online 2 July 2007.
Abstract
Background and purpose:
Blockade of AMPA (
-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 (IC50=5.1-9.0 
M), in vitro. Good anticonvulsant actions were obtained in maximal electroshock-, sound- and chemically-induced seizures (range of ED50=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.
Keywords:
ischaemia, stroke, epilepsy, AMPA, rat, mouse, gerbil
Abbreviations:
4VO, four-vessel occlusion; AMPA, 
-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid; AS, audiogenic seizure; AUC, area under the curve; BCO, bilateral carotid occlusion; DMSO, dimethyl sulphoxide; HPCD, hydroxypropyl-
-cyclodextrin; LDH, lactate dehydrogenase; MCA, middle cerebral artery; MCAO, middle cerebral artery occlusion; MED, minimum effective dose; MES, maximal electroshock; NMDA, N-methyl-D-aspartic acid; PTZ, pentylenetetrazole
