4-[[3-(1,6-dihydro-6-oxo-9-purin-9-yl)-1-oxopropyl]amino]
benzoic acid (AIT-082) is an
hypoxanthine derivative that stimulates in vitro neurite outgrowth and the production of
adenosine and
neurotrophins from astrocytes. These effects may predict an in vivo neuroprotective activity of the drug. Thus, we evaluated whether
AIT-082 protected against a long-term excitotoxicity of hippocampal neurons following
status epilepticus induced in rats by i.p. injection of
kainate (12 mg/kg). The epileptogenic effect of
kainate was evaluated by monitoring behavioral signs and by electroencephalographic (EEG) recording (80% of the animals showed
status epilepticus with a latency of 96.8 +/- 7.4 min starting from the injection). In surviving rats (40% of the injected animals) the neurotoxic effect was evaluated by measuring
glutamic acid decarboxylase (GAD) activity, as an index of loss of hippocampal GABAergic neurons, by evaluating the
body weight after 7 days and by histological examination of hippocampi. The GAD activity was reduced by 44 +/- 8%, and neuronal loss (about 70%) was found in the CA3c, the CA1 area, and in the dentate gyrus. A single dose of
diazepam (20 mg/kg; i.p., 20 min before the
kainate injection) almost completely inhibited both
seizures and neurotoxicity, ensuring survival of animals.
AIT-082 (60 mg/kg/day; i.p., for 7 days, starting from 20 min before the
kainate injection) did not modify the
seizures caused by
kainate but, like
diazepam, it decreased
kainate-induced mortality, the reduction of GAD activity, and the loss of hippocampal neurons. These data confirm that
AIT-082 is of potential interest for the
experimental therapy of
neurodegenerative disorders.