Abstracts

RATIONALE: The molecular mechanisms involved in the neuroprotective effects of antiepileptic drugs are unknown, but growth factors may be involved as endogenous protective mediators. Although brain-derived neurotrophic factor (BDNF) is upregulated in different models of epilepsy, evidence of a relationship with neuroprotection is lacking. For this reason, we investigated whether BDNF synthesis is modulated by antiepileptic drugs. METHODS: BDNF levels were studied with Northern blot, in situ mRNA hybridization and immunoblotting. Rats were treated with pilocarpine (400 mg/kg i.p.) to induce status epilepticus (SE), and then injected with a combination of diazepam (10 mg/kg) and pentobarbital (30 mg/kg), or paraldehyde (0.3 mg/kg) to abort SE 30 min after the beginning of limbic seizures. RESULTS: Hippocampal damage was significantly (p<0.05) lower in diazepam+pentobarbital-treated than in control (saline-treated) animals. BDNF mRNA levels, studied 2 and 24 hours after pilocarpine injection, were moderately increased in saline-treated, but superinduced in diazepam+pentobarbital- or paraldehyde-treated animals, especially in neocortex and hippocampus. Treatment with these drugs in normal animals only slightly increased BDNF levels. BDNF immunoreactivity (IR), investigated 2, 4, 8 and 16 hours after pilocarpine treatment, showed a decrease of mature (14 kDa) and precursor (38 kDa) BDNF isoforms in saline-treated animals, peaking 2 hours after pilocarpine injection and never recovering within the whole period of study. By contrast, when seizures were blocked by diazepam+pentobarbital, BDNF IR greatly increased with a peak at 8 hours after pilocarpine treatment and recovering basal values within the period of study. CONCLUSIONS: These results suggest that neuroprotection by anticonvulsant treatment is related to a strong potentiation of BDNF synthesis in brain regions endangered by seizures.