title: The extracts of Fructus Akebiae, a preparation containing 90% of the active ingredient hederagenin: serotonin, norepinephrine and dopamine reuptake inhibitor.
abstract: Fructus Akebiae is a traditional Chinese herbal extract that has been used for the treatment of depressive disorders in China. Previous studies demonstrated that Fructus Akebiae extracts (FAE) displayed a potent antidepressant-like activity in animal behavior tests and found that the specific active ingredient from the extracts of Fructus Akebiae is hederagenin. However, the underlying mechanism is unknown. Here we provide evidences that FAE enhances the signaling of central monoamines via inhibition of the reuptake of the extracellular monoamines including serotonin (5-HT), norepinephrine (NE) and dopamine (DA). In rat brain membrane preparations and HEK293 cells transfected with human serotonin transporter (SERT), NE transporter (NET) and DA transporter (DAT), we found that FAE displayed marked affinity to rat and cloned human monoamine transporters in ex vivo and in vitro experiments, using competitive radio ligand binding assay. In uptake assays using rat synaptosomes and transfected cells, FAE was found to significantly inhibit all three monoamine transporters in a dose- and time-dependent manner, with a comparable or better potency to their corresponding specific inhibitors. In contrast, FAE (10 μM), showed no significant affinity to a variety array of receptors tested from CNS. In support of our uptake data, in vivo microdialysis studies showed that administration of FAE (12.6, 25, 50 mg/kg) significantly increased extracellular concentrations of 5-HT, NE and DA in frontal cortex of freely moving rats. Taken together, our current study showed for the first time that FAE is a novel triple inhibitor of monoamine transporters, which may be one the mechanisms of its antidepressant activity.
authors: Department of Pharmacology, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, 510515, PR China.
authors: Zeng-Liang
authors: ZL
authors: Jin
authors: Nana
authors: N
authors: Gao
authors: Dan
authors: D
authors: Zhou
authors: Mu-Gen
authors: MG
authors: Chi
authors: Xue-Mei
authors: XM
authors: Yang
authors: Jiang-Ping
authors: JP
authors: Xu
mesh_terms: D000818:Animals; D015306:Biogenic Monoamines / Q000378:metabolism; D001921:Brain / Q000187:drug effects*; D050483:Dopamine Plasma Membrane Transport Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004365:Drugs, Chinese Herbal / Q000737:chemistry / Q000494:pharmacology*; D005625:Frontal Lobe / Q000187:drug effects / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D008297:Male; D009419:Nerve Tissue Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D009474:Neurons / Q000187:drug effects*; D014179:Neurotransmitter Uptake Inhibitors / Q000494:pharmacology*; D050484:Norepinephrine Plasma Membrane Transport Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D009828:Oleanolic Acid / Q000031:analogs & derivatives* / Q000032:analysis / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D050486:Serotonin Plasma Membrane Transport Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D013574:Synaptosomes / Q000187:drug effects* / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D015306:Biogenic Monoamines; D050483:Dopamine Plasma Membrane Transport Proteins; D004365:Drugs, Chinese Herbal; C571811:Fructus Akebiae; D009419:Nerve Tissue Proteins; D014179:Neurotransmitter Uptake Inhibitors; D050484:Norepinephrine Plasma Membrane Transport Proteins; D011994:Recombinant Proteins; C493227:SLC6A2 protein, human; C493214:SLC6A3 protein, human; C493230:SLC6A4 protein, human; D050486:Serotonin Plasma Membrane Transport Proteins; D009828:Oleanolic Acid; C025763:hederagenin