Abstracts

RATIONALE: Nitric oxide (NO) may be involved in the pathophysiological mechanisms of seizure-induced brain damage. Indeed, the concomitant formation of the free radicals, NO and superoxyde leads to the formation of peroxynitrite, a potent oxydant, that can directly damage DNA and activate poly(ADP-ribose) polymerase (PARP). An excessive activation of PARP, has been shown to induce cell death. Thus, we investigated the role of PARP on brain damage after lithium-pilocarpine(li-pilo)-induced status epilepticus (SE) in the rat, using the PARP inhibitor, 3-aminobenzamide. METHODS: Adult male Sprague-Dawley rats, (250-300g, 5 to 7 per group) were subjected to 25 mg/kg pilocarpine, 16-20h after 3 mEq/kg lithium chloride. After 2h of SE, rats received 2.5 mg/kg valium. 3-Aminobenzamide (3AB), 5 or 10 mg/kg, was given ip, 10 min before pilo and 6 h after pilo and then, twice daily until the sacrifice, 7 days after SE. Controls received saline instead of pilo and 3AB. After decapitation, brains were frozen and cut into 20 m thick coronal sections. Brain slices were stained with thionine and neurons were counted using an ocular grid under an optical microscope at X400 magnification. Three sections per animal were examined bilaterally and the number of neurons was counted from the hilus, the CA1 and CA3 subfields of the dorsal hippocampus and from layers 2 and 3-4 of the piriform cortex. RESULTS: Li-pilo-induced SE decreased by 60-80% the number of neurons in CA1, CA3, and hilus of the dorsal hippocampus and piriform cortex, compared to controls. The PARP inhibitor, 3AB, induced at both doses, a significant 54 to 69% increase in the number of neurons in the hilus and CA3 area, compared to rats subjected to li-pilo alone. However, the number of neurons in the CA1 and piriform cortex was not affected by 3AB. CONCLUSIONS: These results suggest that PARP activation may be involved in the mechanisms of epilepsy-induced neuronal injury. However, further studies are needed to confirm the possible neuroprotective effects of PARP inhibitors on epileptic brain damage. Supported by the Institut National de la Sant et de la Recherche M dicale (INSERM U.398).