Riluzole enhances expression of brain-derived neurotrophic factor with consequent proliferation of granule precursor cells in the rat hippocampus.
The dentate gyrus of the hippocampus, generating new cells throughout life, is essential for normal recognition memory performance. Reduction of brain-derived neurotrophic factor (BDNF) in this structure impairs its functions. To elucidate the association between BDNF levels and hippocampal neurogenesis, we first conducted a search for compounds that stimulate endogenous BDNF production in hippocampal granule neurons. Among ion channel modulators tested, riluzole, a neuroprotective agent with anticonvulsant properties that is approved for treatment of amyotrophic lateral sclerosis, was highly effective as a single dose by an intraperitoneal injection, causing a rise in BDNF localized in dentate granule neurons, the hilus, and the stratum radiatum of the CA3 region. Repeated, but not single, injections resulted in prolonged elevation of hippocampal BDNF and were associated with increased numbers of newly generated cells in the granule cell layer. This appeared due to promoted proliferation rather than survival of precursor cells, many of which differentiated into neurons. Intraventricular administration of BDNF-specific antibodies blocked such riluzole effects, suggesting that BDNF increase is necessary for the promotion of precursor proliferation. Our results suggest the basis for a new strategy for treatment of memory dysfunction.
Katoh-Semba
Ritsuko
R
Institute for Developmental Research, Aichi Human Service Center, Kasugai, Aichi 480-0392, Japan. katohsemba@inst-hsc.pref.aichi.jp
Asano
Tomiko
T
Ueda
Hiroshi
H
Morishita
Rika
R
Takeuchi
Ikuo K
IK
Inaguma
Yutaka
Y
Kato
Kanefusa
K
D000818:Animals; D000906:Antibodies / Q000008:administration & dosage / Q000494:pharmacology; D001923:Brain Chemistry; D019208:Brain-Derived Neurotrophic Factor / Q000032:analysis / Q000096:biosynthesis*; D002455:Cell Division / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D006624:Hippocampus / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D007267:Injections; D007276:Injections, Intraventricular; D008954:Models, Biological; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D019782:Riluzole / Q000008:administration & dosage / Q000037:antagonists & inhibitors / Q000276:immunology / Q000494:pharmacology*; D026941:Sodium Channel Blockers / Q000008:administration & dosage / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D013234:Stem Cells / Q000166:cytology / Q000187:drug effects
D000906:Antibodies; D019208:Brain-Derived Neurotrophic Factor; D026941:Sodium Channel Blockers; D019782:Riluzole