Katoh-Semba Ritsuko, Asano Tomiko, Ueda Hiroshi, Morishita Rika, Takeuchi Ikuo K, Inaguma Yutaka, Kato Kanefusa
Institute for Developmental Research, Aichi Human Service Center, Kasugai, Aichi 480-0392, Japan.
FASEB J. 2002 Aug;16(10):1328-30. doi: 10.1096/fj.02-0143fje. Epub 2002 Jun 21.
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.
海马体的齿状回在一生中持续产生新细胞，对正常的认知记忆表现至关重要。该结构中脑源性神经营养因子（BDNF）的减少会损害其功能。为了阐明BDNF水平与海马体神经发生之间的关联，我们首先筛选了能刺激海马体颗粒神经元内源性BDNF产生的化合物。在所测试的离子通道调节剂中，利鲁唑是一种具有抗惊厥特性的神经保护剂，已被批准用于治疗肌萎缩侧索硬化症，腹腔注射单剂量利鲁唑具有高效性，可使齿状颗粒神经元、齿状回门以及CA3区辐射层中的BDNF水平升高。重复注射（而非单次注射）可导致海马体BDNF水平持续升高，并与颗粒细胞层中新生成细胞数量的增加相关。这似乎是由于前体细胞增殖促进而非存活所致，其中许多前体细胞分化为神经元。脑室内注射BDNF特异性抗体可阻断利鲁唑的这种作用，表明BDNF增加是促进前体细胞增殖所必需的。我们的研究结果为治疗记忆功能障碍的新策略奠定了基础。
