PRECLINICAL EVALUATION OF NOVEL ANTICONVULSANT DRUGS

Project: Research project

Description

Investigation of novel antiepileptic drugs in animal seizure models is
being carried out as a complement to studies on the interaction of these
drugs with ion channels in in vitro systems. The anticonvulsant
activities of a noncompetitive (GYKI[52466:
1~(4~aminophenyl)~4~methyl~7,8~methylenedioxy~5H~ 2,3~benzodiazepine) and
a competitive (NBQX: 2,3~dihydroxy~6~nitro~7~
sulfamoyl~benzo[f]quinoxaline) non~NMDA (AMPA~kainate) excitatory amino
acid antagonist were compared in the maximal electroshock (MES) seizure
test and various chemoconvulsant models. Both antagonists were
protective in the MES and pentylenetetrazol tests. GYKI[52466 was also
protective against seizures and lethality induced by 4~aminopyridine,
kainate and AMPA, but not by NMDA, whereas NBQX was ineffective in these
chemoconvulsant tests. Both GYKI[52466 and NBQX produced motor
impairment at doses similar to those that were protective in the MES
test. We conclude that under some circumstances, noncompetitive
AMPA~kainate antagonists could offer advantages over competitive
antagonists in the treatment of seizures. However, neurological toxicity
is an obstacle to the potential clinical use of both classes of agents.
The effectiveness of AMPA~kainate antagonists in standard anticonvulsant
screening models suggests that such compounds could have utility in
epilepsy therapy. Noncompetitive AMPA~kainate antagonists, like
GYKI[52466, may offer advantages over competitive antagonists in certain
seizure types, especially those associated with high synaptic levels of
glutamate.
StatusNot started

Funding

  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health

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Seizures
Anticonvulsants
Epilepsy
Steroids
Neurotransmitter Agents
Progesterone
Menstruation
Pregnanolone
Pentylenetetrazole
GABA-A Receptors
Kainic Acid
Therapeutics
Ion Channels
Finasteride
gamma-Aminobutyric Acid
Animal Models
Status Epilepticus
Progesterone Receptors
alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid
Hormones

Keywords

  • Medicine(all)
  • Neuroscience(all)