Riluzole enhances expression of brain‐derived neurotrophic factor with consequent proliferation of granule precursor cells in the rat hippocampus

Abstract

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.

Soft-diet Feeding Inhibits Adult Neurogenesis in Hippocampus of Mice

“…One of the most effective promoters of neurogenesis in the dentate gyrus is BDNF, which is strongly expressed in the adult hippocampus 10,19) . An enhancement of BDNF production has been shown to enhance neural precursor cell proliferation in the subgranular zone 10) , and a shortage of BDNF content has been linked to a drop in neurogenesis 18) .…”

“…An enhancement of BDNF production has been shown to enhance neural precursor cell proliferation in the subgranular zone 10) , and a shortage of BDNF content has been linked to a drop in neurogenesis 18) . The action of BDNF is mediated by the specific tyrosine kinase receptor TrkB, which is also widely expressed in the dentate gyrus 23) .…”

“…Brain-derived neurotrophic factor (BDNF) plays important roles in the development, plasticity and survival of neurons in the central nervous system 10,19) . Widely distributed throughout the brain, BDNF is expressed at highest levels in the hippocampus and cerebral cortex 5,16) .…”

Antidepressants and Cdk inhibitors: Releasing the brake on neurogenesis?

“…For example, brain-derived neurotrophic factor (BDNF) enhances hippocampal proliferation, an effect that is blocked by BDNF-specific antibodies. 39 Insulinlike growth factor 1 (IGF-1), 40 transforming growth factor (TGF), vascular endothelial growth factor (VGEF) and others growth factors have been shown to induce proliferation in the dentate gyrus. [41][42][43][44][45] The Wnt signaling pathway was identified to induce neurogenesis in the dentate gyrus.…”

Hippocampal N-Acetylaspartate Concentration and Response to Riluzole in Generalized Anxiety Disorder

“…When stress-related glutamatergic dysregulation results in excessive glutamate accumulation in the synapse, glutamatergic neurotoxicity or "excitotoxicity," culminating in neuronal death, has been observed (e.g., 9,10). Riluzole has a complex mechanism of action, including: (1) inhibition of voltage-dependent sodium channels in central nervous system (CNS) neurons (11,12); (2) inhibition of excitotoxic injury (13); (3) increased glutamate reuptake (14); (4) stimulation of growth factor synthesis, including brain-derived neurotrophic factor (BDNF) (15,16); (5) promotion of neuritogenesis, neurite branching, and neurite outgrowth (17); and (6) enhancement of hippocampal AMPA receptor subunit (GluR1 and GluR2) expression (18).…”