title: An AMPA receptor potentiator modulates hippocampal expression of BDNF: an in vivo study.
abstract: AMPA receptor activation has been demonstrated to increase the neuronal expression of brain derived neurotrophic factor (BDNF). In the present study, we investigated the effect of a novel AMPA receptor potentiator (LY404187) and its active isomer (LY451646) on the expression of BDNF protein and mRNA, as well as TrkB mRNA in rat hippocampus. LY404187 administered for 7 days (1 mg/kg) significantly increased the number of BDNF immunopositive cells in the dentate gyrus, but not other hippocampal subfields. Chronic treatment (7 days) with LY451646 (0.5 mg/kg, comparable to 1 mg/kg of LY404187) increased the level of both BDNF and TrkB mRNA expression in the dentate gyrus, CA3 and CA4 of the hippocampus. However, chronic treatment with lower doses of LY451646 (0.125 and 0.25 mg/kg) decreased the level of BDNF and TrkB mRNA in hippocampus, whilst the highest used dose of LY451646 (1 mg/kg) had no effect on BDNF and TrkB mRNA in hippocampus. In contrast, acute treatment with LY451646 produced an increase in BDNF mRNA levels at doses of 0.125 and 0.25 mg/kg in the hippocampus (CA4, CA3 and dentate gyrus, but not in CA1). LY451646 at 0.5 mg/kg had no effect, but at 1.0 mg/kg decreased the level of BDNF mRNA in hippocampus. Acute treatment with LY451646 did not affect the TrkB receptor mRNA levels in hippocampus. Our results demonstrate that biarylpropylsulfonamide AMPA receptor potentiators are capable of modulating the expression of BDNF and TrkB mRNA in a dose- and time-dependent manner. The increase in both BDNF protein and mRNA expression in the dentate gyrus but not in CA1 indicates a specific role of AMPA receptors in the regulation of BDNF expression in this hippocampal subfield. The regulation of BDNF expression by biarylpropylsulfonamids such as LY451646 may have important therapeutical implications for this class of molecule in the treatment of depression and other CNS disorders.
authors.affiliation: Eli Lilly and Co Ltd, Lilly Corporate Center, Indianapolis, IN 46285-0814, USA. mackow@if-pan.krakow.pl
authors.forename: Marzena
authors.initials: M
authors.lastname: Mackowiak
authors.forename: Michael J
authors.initials: MJ
authors.lastname: O'Neill
authors.forename: Caroline A
authors.initials: CA
authors.lastname: Hicks
authors.forename: David
authors.initials: D
authors.lastname: Bleakman
authors.forename: Phil
authors.initials: P
authors.lastname: Skolnick
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000096:biosynthesis / Q000187:drug effects* / Q000235:genetics; D018891:Dentate Gyrus / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D006624:Hippocampus / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D020813:Receptor, trkB / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D018091:Receptors, AMPA / Q000819:agonists* / Q000235:genetics; D013237:Stereoisomerism; D013449:Sulfonamides / Q000737:chemistry / Q000494:pharmacology*; D013997:Time Factors
chemical_list: D019208:Brain-Derived Neurotrophic Factor; C430915:LY 404187; D018091:Receptors, AMPA; D013449:Sulfonamides; D020813:Receptor, trkB