Comparison of the AMPA Antagonist Action of New 2,3-Benzodiazepines in Vitro and Their Neuroprotective Effects in Vivo

Gábor Kapus, Szabolcs Kertész, Gábor Gigler, Annamária Simó, Miklos Vegh, József Barkóczy, L. Hársing, Géza Szabó, György Lévay

Research output: Contribution to journalArticle

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Abstract

Purpose. 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.

Original languageEnglish
Pages (from-to)317-323
Number of pages7
JournalPharmaceutical Research
Volume21
Issue number2
DOIs
Publication statusPublished - Feb 2004

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alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid
AMPA Receptors
Neuroprotective Agents
Benzodiazepines
Neurons
Halogen compounds
Population
Halogens
Gerbillinae
Kainic Acid
Neurology
Cell death
GABA-A Receptors
Retina
Rats
Chickens
Cell Death
Ischemia
Central Nervous System
Data storage equipment

Keywords

  • 2,3-benzodiazepines
  • AMPA antagonists
  • Cerebral ischemia
  • EGIS-9879
  • Neuroprotection

ASJC Scopus subject areas

  • Chemistry(all)
  • Pharmaceutical Science
  • Pharmacology

Cite this

Comparison of the AMPA Antagonist Action of New 2,3-Benzodiazepines in Vitro and Their Neuroprotective Effects in Vivo. / Kapus, Gábor; Kertész, Szabolcs; Gigler, Gábor; Simó, Annamária; Vegh, Miklos; Barkóczy, József; Hársing, L.; Szabó, Géza; Lévay, György.

In: Pharmaceutical Research, Vol. 21, No. 2, 02.2004, p. 317-323.

Research output: Contribution to journalArticle

Kapus, Gábor ; Kertész, Szabolcs ; Gigler, Gábor ; Simó, Annamária ; Vegh, Miklos ; Barkóczy, József ; Hársing, L. ; Szabó, Géza ; Lévay, György. / Comparison of the AMPA Antagonist Action of New 2,3-Benzodiazepines in Vitro and Their Neuroprotective Effects in Vivo. In: Pharmaceutical Research. 2004 ; Vol. 21, No. 2. pp. 317-323.
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