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 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.
Di Iorio
P
P
Department of Biomedical Sciences, University of Chieti, Chieti, Italy.
Virgilio
A
A
Giuliani
P
P
Ballerini
P
P
Vianale
G
G
Middlemiss
P J
PJ
Rathbone
M P
MP
Ciccarelli
R
R
D062365:Aminobenzoates; D000704:Analysis of Variance; D000818:Animals; D002470:Cell Survival / Q000187:drug effects; D018891:Dentate Gyrus / Q000187:drug effects / Q000473:pathology / Q000502:physiology; D003975:Diazepam / Q000494:pharmacology; D004569:Electroencephalography / Q000187:drug effects*; D005145:Face; D005968:Glutamate Decarboxylase / Q000378:metabolism; D006624:Hippocampus / Q000187:drug effects / Q000473:pathology / Q000502:physiology*; D007042:Hypoxanthines; D007608:Kainic Acid / Q000633:toxicity*; D008297:Male; D009043:Motor Activity / Q000187:drug effects / Q000502:physiology; D009055:Mouth; D009474:Neurons / Q000187:drug effects / Q000473:pathology / Q000502:physiology*; D018696:Neuroprotective Agents / Q000494:pharmacology*; D011687:Purines / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012640:Seizures / Q000139:chemically induced / Q000503:physiopathology / Q000517:prevention & control*; D013226:Status Epilepticus / Q000139:chemically induced / Q000503:physiopathology* / Q000517:prevention & control*; D013997:Time Factors; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
D062365:Aminobenzoates; D007042:Hypoxanthines; D018696:Neuroprotective Agents; D011687:Purines; C086241:4-((3-(1,6-dihyro-6-oxo-9H-purin-9-yl)-1-oxopropyl)amino)benzoic acid; D005680:gamma-Aminobutyric Acid; D005968:Glutamate Decarboxylase; D003975:Diazepam; D007608:Kainic Acid