title: Activation of hippocampal BDNF signaling is involved in the antidepressant-like effect of the NMDA receptor antagonist 7-chlorokynurenic acid.
abstract: Previous studies showed that acute 7-chlorokynurenic acid treatment produced a rapid antidepressant-like action in depression-like animal models. However, the underlying mechanism involved in neurotrophin system about 7-chlorokynurenic acid is unclear. Our present study aimed to verify whether chronic 7-chlorokynurenic acid treatment produced an antidepressant-like effect through the activation of brain-derived neurotrophic factor (BDNF) signaling in mice exposed to chronic unpredictable mild stress (CUMS). In addition, we performed an oral toxicological evaluation of chronic 7-chlorokynurenic acid administration in mice. The results showed that a two-week administration with 7-chlorokynurenic acid reversed the decreased sucrose preference and prolonged first feeding latency. In addition, 7-chlorokynurenic acid significantly reversed the CUMS-induced down-regulation of BDNF, p-ERK, p-Akt, PSD-95, synapsin I and cell proliferation in the hippocampus. In contrast, K252a, an inhibitor of BDNF receptor tropomyosin-related kinase receptor B (TrkB), blocked the antidepressant-like effect and the improvement of 7-chlorokynurenic acid. Furthermore, we found that 7-chlorokynurenic acid did not produce any toxicological effect in mice. In conclusion, our findings suggest that the antidepressant-like effect of 7-chlorokynurenic acid may be mediated, at least in part, by activating BDNF signaling in the hippocampus.
authors.affiliation: Xiamen Hospital of Traditional Chinese Medicine, Xiamen 361009, Fujian Province, PR China. Electronic address: lichengfu103@126.com.
authors.forename: Cheng-Fu
authors.initials: CF
authors.lastname: Li
authors.affiliation: Xiamen Hospital of Traditional Chinese Medicine, Xiamen 361009, Fujian Province, PR China.
authors.forename: Xue-Mei
authors.initials: XM
authors.lastname: Chen
authors.affiliation: Xiamen Hospital of Traditional Chinese Medicine, Xiamen 361009, Fujian Province, PR China.
authors.forename: Shao-Mei
authors.initials: SM
authors.lastname: Chen
authors.affiliation: Department of Chemical and Pharmaceutical Engineering, Huaqiao University, Xiamen 361021, Fujian Province, PR China.
authors.forename: Rong-Hao
authors.initials: RH
authors.lastname: Mu
authors.affiliation: Department of Chemical and Pharmaceutical Engineering, Huaqiao University, Xiamen 361021, Fujian Province, PR China.
authors.forename: Bin-Bin
authors.initials: BB
authors.lastname: Liu
authors.affiliation: Department of Chemical and Pharmaceutical Engineering, Huaqiao University, Xiamen 361021, Fujian Province, PR China.
authors.forename: Liu
authors.initials: L
authors.lastname: Luo
authors.affiliation: Department of Chemical and Pharmaceutical Engineering, Huaqiao University, Xiamen 361021, Fujian Province, PR China.
authors.forename: Xiao-Long
authors.initials: XL
authors.lastname: Liu
authors.affiliation: Department of Chemical and Pharmaceutical Engineering, Huaqiao University, Xiamen 361021, Fujian Province, PR China; Institute of Pharmaceutical Engineering, Huaqiao University, Xiamen 361021, Fujian Province, PR China.
authors.forename: Di
authors.initials: D
authors.lastname: Geng
authors.affiliation: Department of Chemical and Pharmaceutical Engineering, Huaqiao University, Xiamen 361021, Fujian Province, PR China; Institute of Pharmaceutical Engineering, Huaqiao University, Xiamen 361021, Fujian Province, PR China.
authors.forename: Qing
authors.initials: Q
authors.lastname: Liu
authors.affiliation: Department of Chemical and Pharmaceutical Engineering, Huaqiao University, Xiamen 361021, Fujian Province, PR China; Institute of Pharmaceutical Engineering, Huaqiao University, Xiamen 361021, Fujian Province, PR China.
authors.forename: Li-Tao
authors.initials: LT
authors.lastname: Yi
mesh_terms: D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology* / Q000633:toxicity; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism*; D003866:Depressive Disorder / Q000188:drug therapy* / Q000378:metabolism; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical; D006624:Hippocampus / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D007668:Kidney / Q000187:drug effects / Q000473:pathology; D007736:Kynurenic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000633:toxicity; D008099:Liver / Q000187:drug effects / Q000473:pathology; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008297:Male; D008813:Mice, Inbred ICR; D011897:Random Allocation; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013315:Stress, Psychological / Q000188:drug therapy / Q000378:metabolism; D035501:Uncertainty
chemical_list: D000928:Antidepressive Agents; D019208:Brain-Derived Neurotrophic Factor; D016194:Receptors, N-Methyl-D-Aspartate; D007736:Kynurenic Acid; C057013:7-chlorokynurenic acid
keywords: 7-Chlorokynurenic acid; Brain-derived neurotrophic factor; Depression; Toxicological evaluation