A possible mechanism underlying an antidepressive-like effect of Kososan, a Kampo medicine, via the hypothalamic orexinergic system in the stress-induced depression-like model mice.
Kososan, a Kampo (Japanese herbal) medicine, has an antidepressive-like effect in behavioral animal models of depression and has been used clinically for the improvement of depressive mood. However, mechanism(s) underlying the antidepressive-like effect of kososan remain unknown. Previous studies showed that orexin-A (OX-A), a neuropeptide that is involved in feeding and arousal, exhibits an antidepressive-like property via hippocampal cell proliferation. Here, we used immunohistochemical analysis with bromodeoxyuridine (BrdU), a marker of proliferating cells, to investigate the effect of long-term treatment with kososan on the orexinergic system and on hippocampal cell proliferation. Oral administration of kososan (1.0 g/kg) or milnacipran (60 mg/kg), a serotonin and noradrenaline reuptake inhibitor, for 28 d led to an antidepressive-like effect in the stress-induced depression-like model mice and reversed the stress-induced decrease in the number of OX-A-positive cells in the lateral hypothalamic area. In addition, both kososan and milnacipran alleviated the stress-induced decrease in the number of BrdU-positive cells in the hippocampal dentate gyrus. Moreover, the antidepressive-like effect and the increase in cell proliferation and in the number of neuropeptide Y (NPY, which is closely associated with orexinergic system)-positive cells in the dentate gyrus induced by kososan were blocked by treatment with SB-334867, an orexin receptor 1 antagonist. These results suggest that kososan exerts an antidepressive-like effect via the improvement of the stress-induced decrease in hippocampal cell proliferation and that the mechanism underlying the antidepressive-like effect of kososan, but not of milnacipran, may be associated with the regulation of orexinergic and/or NPYergic transmission.
Department of Clinical Research, Oriental Medicine Research Center, Kitasato University, Tokyo 108-8642, Japan.
Naoki
N
Ito
Takeshi
T
Yabe
Takayuki
T
Nagai
Tetsuro
T
Oikawa
Haruki
H
Yamada
Toshihiko
T
Hanawa
D000818:Animals; D001973:Bromodeoxyuridine / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D003521:Cyclopropanes / Q000494:pharmacology / Q000627:therapeutic use; D003863:Depression / Q000188:drug therapy* / Q000378:metabolism; D004195:Disease Models, Animal; D004365:Drugs, Chinese Herbal / Q000494:pharmacology / Q000627:therapeutic use*; D006624:Hippocampus / Q000187:drug effects*; D007031:Hypothalamus / Q000187:drug effects*; D047908:Intracellular Signaling Peptides and Proteins / Q000819:agonists* / Q000378:metabolism; D019684:Magnoliopsida; D008297:Male; D020835:Medicine, Kampo; D051379:Mice; D008815:Mice, Inbred Strains; D000078764:Milnacipran; D009478:Neuropeptide Y / Q000378:metabolism; D009479:Neuropeptides / Q000819:agonists* / Q000378:metabolism; D018377:Neurotransmitter Agents / Q000494:pharmacology / Q000627:therapeutic use*; D009638:Norepinephrine / Q000378:metabolism; D000068797:Orexins; D008517:Phytotherapy; D012701:Serotonin / Q000378:metabolism; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D013315:Stress, Psychological / Q000188:drug therapy / Q000378:metabolism
D001973:Bromodeoxyuridine; D003521:Cyclopropanes; D004365:Drugs, Chinese Herbal; D047908:Intracellular Signaling Peptides and Proteins; D000078764:Milnacipran; D009478:Neuropeptide Y; D009479:Neuropeptides; D018377:Neurotransmitter Agents; D009638:Norepinephrine; D000068797:Orexins; D012701:Serotonin; D017367:Selective Serotonin Reuptake Inhibitors; C400346:koso-san