Comparison of the AMPA antagonist action of new 2,3-benzodiazepines in vitro and their neuroprotective effects in vivo.
OBJECTIVE
AMPA receptor-mediated excitotoxicity is thought to be a critical process in diseases accompanied by neuronal cell loss following a hypoxic/anoxic state of the central nervous system. It has been suggested that blockade of AMPA receptors might result in significant protection of neurons against cellular damage. For testing the hypothesis, in vitro efficacy and in vivo neuroprotective action of new 2,3-benzodiazepine (2,3BDZ) AMPA antagonists have been compared.


METHODS
2.3BDZs were tested on kainate-evoked whole-cell currents in cultured neurons as well as on population spikes (PS) in rat hippocampal slices. Data were correlated with those obtained from the spreading depression (SD) experiments in chicken retina. Compounds were also examined in the gerbil bilateral carotid occlusion model (BCO), where percentage decrease of ischemia-related hypermotility (HM), impaired spatial memory (SA), and hypoxia-induced hippocampal CA1 neuronal cell death (CA1) were evaluated.


RESULTS
Certain structural modifications of classical 2,3BDZs resulted in increased in vitro activity and improved in vivo efficacy. In particular, the halogen-substituted compounds EGIS-9879 and EGIS-9883 showed the highest neuroprotective efficacy (84% and 47% protection in CA1, 71% and 82% decrease in HM, respectively; 4 x 5 mg/kg i.p.) in BCO. PS and SD were correlated to the decrease of neuronal loss in the CA1 area. Lack of significant correlation was found between PS and CA1 (r = 0.437, p = 0.079) or SD and CA1 (r = 0.380, p = 0.146).


CONCLUSIONS
Several new 2.3BDZ AMPA receptor antagonists have been synthesized at EGIS Pharmaceuticals characterized by remarkable in vitro and corresponding in vivo neuroprotective properties.
Kapus
Gábor
G
EGIS Pharmaceuticals Ltd., H-1475 Budapest 10, POB 100, Hungary.
Kertész
Szabolcs
S
Gigler
Gábor
G
Simó
Annamária
A
Vegh
Miklos
M
Barkóczy
József
J
Hársing
László G
LG
Szabó
Géza
G
Lévay
György
G
D000200:Action Potentials; D000818:Animals; D001157:Arterial Occlusive Diseases / Q000150:complications; D001522:Behavior, Animal / Q000187:drug effects; D001569:Benzodiazepines / Q000494:pharmacology*; D002340:Carotid Artery Diseases / Q000150:complications; D016923:Cell Death / Q000187:drug effects; D002478:Cells, Cultured; D002645:Chickens; D005849:Gerbillinae; D006624:Hippocampus / Q000187:drug effects* / Q000473:pathology / Q000502:physiology; D002534:Hypoxia, Brain / Q000209:etiology / Q000473:pathology; D066298:In Vitro Techniques; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D009043:Motor Activity / Q000187:drug effects; D018696:Neuroprotective Agents / Q000494:pharmacology*; D018408:Patch-Clamp Techniques; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D018091:Receptors, AMPA / Q000037:antagonists & inhibitors* / Q000378:metabolism / Q000502:physiology; D012160:Retina / Q000187:drug effects / Q000502:physiology; D009435:Synaptic Transmission / Q000187:drug effects
D018696:Neuroprotective Agents; D018091:Receptors, AMPA; D001569:Benzodiazepines