egis-8332 and Seizures

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.. 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.. 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.. 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.

Topics: alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; Animals; Anticonvulsants; Benzodiazepines; Brain; Brain Ischemia; Cells, Cultured; Disease Models, Animal; Dose-Response Relationship, Drug; Excitatory Amino Acid Agonists; Gerbillinae; Male; Membrane Potentials; Mice; Mice, Inbred DBA; Neurons; Neuroprotective Agents; Patch-Clamp Techniques; Purkinje Cells; Quisqualic Acid; Rats; Rats, Sprague-Dawley; Rats, Wistar; Receptors, AMPA; Seizures; Telencephalon; Time Factors

Alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor antagonists have been shown to have neuroprotective effects in stroke models and although clinical trials with some agents are still ongoing, published results have not been favourable. We therefore wished to compare the effects of GYKI 52466, GYKI 53405, EGIS-8332 and EGIS-10608, non-competitive AMPA receptor antagonists with homophthalazine chemical structures, in standard animal stroke models with effects in a neurodegenerative model--excitoxicity in newborn mice. All compounds inhibited the S-AMPA-induced spreading depression in the chicken retina, in vitro, and were potent anticonvulsants against maximal electroshock in mice, in vivo. The AMPA receptor antagonists prevented domoate-induced cell death of motoneurons, in vitro, and reduced infarct size in a dose-dependent manner in the permanent middle cerebral artery occlusion model in mice, in vivo. In newborn mice (P5, histopathology at P10), local injection of the AMPA receptor agonist S-bromo-willardiine at day 5 after birth induced cortical damage and white matter damage, which was reduced in a dose-dependent manner by the AMPA receptor antagonists. EGIS 10608 was a very powerful receptor antagonist of white matter damage. In contrast, GYKI 52466 did not antagonize cortical and white matter damage induced by ibotenic acid. These models allow quantification of the effects of AMPA receptor antagonists in vitro and in vivo.

Topics: Animals; Animals, Newborn; Anticonvulsants; Benzodiazepines; Brain; Brain Ischemia; Cell Survival; Chickens; Cortical Spreading Depression; Disease Models, Animal; Dose-Response Relationship, Drug; Electroshock; Excitatory Amino Acid Antagonists; Infarction, Middle Cerebral Artery; Male; Mice; Mice, Inbred Strains; Motor Neurons; Nerve Degeneration; Quinoxalines; Rats; Rats, Sprague-Dawley; Receptors, AMPA; Retina; Seizures; Stroke