AIT-082 is neuroprotective against kainate-induced neuronal injury in rats

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 outgrow th 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 e valuated 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 t he injected animals) the neurotoxic effect was evaluated by measuring gluta mic acid decarboxylase (GAD) activity, as an index of loss of hippocampal G ABAergic neurons, by evaluating the body weight after 7 days and by histolo gical 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 neuro toxicity, ensuring survival of animals. AIT082 (60 mg/kg/day; i.p., for 7 d ays, 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 neur ons. These data confirm that AIT-OS2 is of potential interest for the exper imental therapy of neurodegenerative disorders. (C) 2001 Academic Press.