Tonic-clonic seizures induce division of neuronal progenitor cells with concomitant changes in expression of neurotrophic factors in the brain of pilocarpine-treated mice.

Epileptic seizures cause severe and long-lasting events on the architecture of the brain, including neuronal cell death, accompanied neurogenesis, reactive gliosis, and mossy fiber sprouting. However, it remains uncertain whether these functional and anatomical alterations are associated with the development of hyperexcitability, or as inhibitory processes. Neurotrophic factors are probable mediators of these pathophysiological events. The present study was designed to clarify the role of various neurotrophic factors on the pilocarpine model of seizures. At 4 h following pilocarpine-induced seizures, expression of NGF, BDNF, HB-EGF, and FGF-2 increased only in the mice manifesting tonic-clonic convulsions and not in mice without seizures. NT-3 expression decreased in pilocarpine-treated mice experiencing seizures, tonic-clonic or not, compared to mice with no seizures. Neuronal cell damage, which was evident by Fluoro-Jade B staining, was observed within 24 h in the mice exhibiting tonic-clonic seizures, followed by an increase in the number of BrdU-positive cells and glial cells, which were evident after 2 days. None of these pathophysiological changes occurred in the mice which showed no seizures, although they were injected with pilocarpine, nor in the activated epilepsy-prone EL mice, which experienced repeated severe seizures. Together, these results suggest that neuronal damage occurring in the brain of the mice manifesting tonic-clonic seizures is accompanied by neurogenesis. This sequence of events may be regulated through changes in expression of neurotrophic factors such as NGF, BDNF, HB-FGF, and NT-3.

Role of histaminergic neurons in development of epileptic seizures in EL mice.

The EL mouse is an animal model for hereditary temporal lobe epilepsy. When the mice receive weekly vestibular stimulation, e.g., 30 "tosses", 10-15 cm vertically, they start to convulse after 1-2 weeks. The aim of this study was to evaluate the role of the histaminergic neurons in the regulation of seizure development in the EL mice. The obtained results indicated that administration of either histidine, a substrate for histamine synthesis, or metoprine (2,4-diamino-5-(3,4-dichlorophnyl)-6-methyl-pyrimidine), an inhibitor of histamine N-methyltransferase (HNMT), retarded the onset of seizure episodes in the mice. The co-administration of histidine and metoprine caused a more marked delay in it. The histamine levels in the brain significantly increased in response to any of these treatments. The intraperitoneal injection of diphenhydramine, a H1-antagonist accelerated the initiation of seizure episodes in the mice, whereas thioperamide, a H3-antagonist caused a delay in the response. There were significant increases in the brain histamine levels upon injection of any of these drugs with concomitant rises in the activity of the histidine decarboxylase (HDC). These results, taken together, suggest that the histaminergic neurons play crucial roles in the development of seizures in the EL mice. They inhibit convulsion in a H1-dependent fashion, while the neurons enhance it in a H3-receptor-mediated way.

Increased expression of mitochondrial respiratory enzymes in the brain of epilepsy-prone, naive EL mice.

The present studies demonstrate that expression of both type 5 and type 6 subunits of NADH dehydrogenase and the type 1 subunit of cytochrome oxidase is enhanced significantly in the brains of naive, epilepsy-prone EL mice. In contrast, no apparent change in expression occurred with type 1 and type 2 subunits of NADH dehydrogenase. When expression of type 5 and 6 subunits of NADH dehydrogenase was determined at 24 h after a single series of vestibular stimulation, significant down-regulation was detected. The expression of subunit 2 of NADH dehydrogenase augmented gradually after vestibular stimulation. The increased expression of these mitochondrial respiratory enzymes may reflect enhanced demand for energy due to inherent, spontaneous neuronal hyperactivity in the brains of EL mice.