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There is growing evidence that free radical generation may play a key role in the neuronal damage induced by prolonged convulsions. Free radical scavengers are known to inhibit neuronal death induced by exposure to excitotoxins. However, this neuroprotective effect has not been demonstrated with treatment after seizures had been stopped. We investigated whether 3-methyl-1-phenyl-2-pyrazolin-5-one, edaravone (Ed), a newly developed free radical scavenger that has been used clinically to treat cerebral infarction, could prevent neuronal loss when administered after the occurrence of seizures in a kainic acid (KA)-induced seizure model. Compared with KA alone, cell loss was significantly reduced when animals received Ed (10 mg/kg i.v.) just after seizures, and when Ed was administered both 60 min before (30 mg/kg i.p.) and after KA injection. Combined before-and-after treatment with Ed significantly ameliorated the KA-induced decrease of glutathione and blocked the KA-induced increase of 4-hydroxy-2-nonenal (HNE). Because before-and-after treatment with Ed significantly lessened the KA-induced increase of HNE, Ed may exert its neuroprotective effect by inhibiting lipid peroxidation. However, post-treatment with Ed prevented neuronal cell loss, while HNE and glutathione levels did not differ from those in animals without Ed, so a mechanism other than free radical scavenging must be involved in the prevention of cell loss. Patients who develop status epilepticus are unlikely to receive adequate antioxidant therapy before the onset, so it is an advantage that Ed can prevent neuronal death even when administered after seizures.

Structural rearrangement and synaptic reorganization are known to occur in the brain after seizures. If neuronal rearrangement after seizures always results in abnormal hyperexcitability, it would provide an accurate pathway to the appropriate target and as a result, it may be the mechanism of epileptogenesis. This study examined the mechanism of axon guidance in the mature rat brain after seizures by evaluating the expression of the axonal guidance molecule, neuropilin-2. We assessed the expression of neuropilin-2 by northern blotting and immunohistochemistry in rat with seizures created by kindling stimulation and kainate injection.The neuropilin-2 mRNA level was increased in the whole brain of the rats at 24 h after either type of seizure. Neuropilin-2 mRNA was not increased at 2 weeks after the last stimulation. Immunohistochemistry demonstrated that neuropilin-2 protein was increased in the dentate gyrus and the entorhinal cortex in the both seizure models. These findings suggested that there was overexpression of neuropilin-2 in the brains of mature rats with different types of seizure. Accordingly, neuropilin-2 might regulate remodeling after seizures as it does during the development of the hippocampal formation. Our findings suggest that axons may not project and outgrow 'aberrantly' after seizures, but may be regulated by the chemorepellent effect through neuropilin-2.

To investigate the regulatory role of tetrahydrobiopterin in neurotransmitter amine biosynthesis, 2,4-diamino-6-hdyroxypyrimidine, a potent inhibitor of guanosine triphosphate cyclohydrolase which is a rate-limiting enzyme of tetrahydrobiopterin biosynthesis, was administered intraperitoneally to weanling rats. Four h after 4 injections at 4-h intervals, the biopterin contents in plasma and liver were reduced to the level of 9 and 3.5%, respectively, of those in the control group injected with saline; while the contents in the whole brain, neocortex + striatum, diencephalon, and brainstem were 34, 50, 33 and 28%, respectively, of the control level. When in vivo tyrosine and tryptophan hydroxylase activities were measured over a 30-min period after the inhibition of aromatic amino acid decarboxylase, the accumulation of dihydroxyphenylalanine was reduced to 74, 77, 67 and 69% of the control in the whole brain, neocortex + striatum, diencephalon, and brainstem, respectively; and the accumulation of 5-hydroxytryptophan, to 71, 74, 66 and 65% of the control, respectively. On the other hand, 5-hydroxytryptamine and 5-hydroxyindole acetic acid contents were not altered in any brain regions, although norepinephrine and dopamine contents were reduced to approximately 70% of the control in the brainstem and the contents of dopamine metabolites were significantly decreased in the diencephalon and brainstem. Plasma phenylalanine level was significantly elevated, while the plasma tyrosine level was reduced, compared with the control level of these amino acids. These results indicate that the drug-treated rats could be an animal model for tetrahydrobiopterin-deficient disease involving neurological disorder.