Electroconvulsive seizure, but not imipramine, rapidly up-regulates pro-BDNF and t-PA, leading to mature BDNF production, in the rat hippocampus.
Electroconvulsive therapy is the most effective treatment for antidepressant-resistant depression, although its mechanism has not been fully elucidated. Previous studies have demonstrated that electroconvulsive seizures (ECS) induce expression of brain-derived neurotrophic factor (BDNF) in the rat hippocampus. However, in contrast with mature BDNF (mBDNF) known to have antidepressant effects, its precursor (pro-BDNF) has harmful effects on neurons. We therefore hypothesized that efficient processing of pro-BDNF is a critical requirement for the antidepressant effects of ECS. We found that single administration of ECS rapidly increased not only hippocampal levels of pro-BDNF but also those of prohormone convertase 1 (PC1) and tissue-plasminogen activator (t-PA), which are proteases involved in intra- and extracellular pro-BDNF processing, respectively. Interestingly, pro-BDNF and t-PA levels were increased in hippocampal synaptosomes after single ECS, suggesting their transport to secretory sites. In rats receiving 10-d repeated ECS, accumulation of pro-BDNF and a resultant increase in mBDNF levels were observed. While t-PA levels increased and accumulated following repeated ECS, PC1 levels did not, suggesting that intracellular processing capacity is limited. Finally, chronic administration of imipramine significantly increased mBDNF levels, but not pro-BDNF and protease levels, indicating that the therapeutic mechanism of imipramine differs from that of ECS. Taken together, these results suggest that, while intra- and extracellular proteases are involved in pro-BDNF processing in single ECS, t-PA plays a dominant role following repeated ECS. Such efficient pro-BDNF processing as well as strong induction of BDNF expression may contribute to the antidepressant effects of ECS.
Department of Psychiatry and Neurosciences, Division of Frontier Medical Science, Programs for Biomedical Research, Graduate School of Biomedical Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima, Japan.
Masahiro
M
Segawa
Shigeru
S
Morinobu
Tomoya
T
Matsumoto
Manabu
M
Fuchikami
Shigeto
S
Yamawaki
D000818:Animals; D000929:Antidepressive Agents, Tricyclic / Q000494:pharmacology; D019208:Brain-Derived Neurotrophic Factor / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D004597:Electroshock / Q000009:adverse effects; D006624:Hippocampus / Q000000981:diagnostic imaging / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D007099:Imipramine / Q000494:pharmacology; D047468:Immunoprecipitation; D008297:Male; D045664:Proprotein Convertase 1 / Q000235:genetics / Q000378:metabolism; D011498:Protein Precursors / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D012640:Seizures / Q000209:etiology / Q000473:pathology*; D013574:Synaptosomes / Q000187:drug effects / Q000378:metabolism; D013997:Time Factors; D010959:Tissue Plasminogen Activator / Q000378:metabolism*; D014463:Ultrasonography; D015854:Up-Regulation / Q000187:drug effects / Q000502:physiology*
D000929:Antidepressive Agents, Tricyclic; D019208:Brain-Derived Neurotrophic Factor; D011498:Protein Precursors; D012333:RNA, Messenger; C426674:brain-derived neurotrophic factor precursor; D010959:Tissue Plasminogen Activator; D045664:Proprotein Convertase 1; D007099:Imipramine