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.
Hagihara
Hideo
H
Nagoya University Bioscience and Biotechnology Center, Chikusa, Nagoya 464-8601, Japan.
Hara
Mizumi
M
Tsunekawa
Kyouko
K
Nakagawa
Yukinori
Y
Sawada
Makoto
M
Nakano
Kiwao
K
D000161:Acoustic Stimulation / Q000379:methods; D000367:Age Factors; D000818:Animals; D015152:Blotting, Northern / Q000379:methods; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D001973:Bromodeoxyuridine / Q000378:metabolism; D039481:CD11b Antigen / Q000378:metabolism; D002455:Cell Division / Q000187:drug effects*; D005260:Female; D005452:Fluoresceins; D005786:Gene Expression Regulation / Q000187:drug effects; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D006651:Histocytochemistry / Q000379:methods; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009414:Nerve Growth Factors / Q000145:classification / Q000235:genetics / Q000378:metabolism*; D009474:Neurons / Q000166:cytology* / Q000187:drug effects; D009930:Organic Chemicals / Q000378:metabolism; D010751:Phosphopyruvate Hydratase / Q000378:metabolism; D010862:Pilocarpine / Q000494:pharmacology*; D012333:RNA, Messenger / Q000096:biosynthesis; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D012640:Seizures / Q000139:chemically induced / Q000473:pathology* / Q000503:physiopathology; D013234:Stem Cells / Q000187:drug effects*
D039481:CD11b Antigen; D005452:Fluoresceins; D005904:Glial Fibrillary Acidic Protein; D009414:Nerve Growth Factors; D009930:Organic Chemicals; D012333:RNA, Messenger; C435731:fluoro jade; D010862:Pilocarpine; D010751:Phosphopyruvate Hydratase; D001973:Bromodeoxyuridine