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Ketamine ameliorates depressive-like behaviors by tPA-mediated conversion of proBDNF to mBDNF in the hippocampus of stressed rats.

Fan Zhang, Jie Luo, Xianlin Zhu

Psychiatry Research November 2018 DOI: 10.1016/j.psychres.2018.08.075 (opens in new tab)

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AI-extracted from the abstract
Characteristics Animal experimental study Peer reviewed
Population Rats subjected to chronic unpredicted mild stress (CUMS) as a depression model
Intervention Ketamine
Topics Depression Ketamine Esketamine
Keywords Brain-derived neurotrophic factor Plasminogen activator inhibitor-1 Tissue plasminogen activator
Key findings Ketamine reversed stress-induced reductions in sucrose preference and locomotor activity in rats and lowered the hippocampal proBDNF/mBDNF ratio while increasing tPA levels. Intrahippocampal injection of an active plasminogen activator inhibitor-1 before ketamine reversed these antidepressant effects and upregulated the proBDNF/mBDNF ratio, suggesting ketamine's antidepressant action may be related to tPA-mediated conversion of proBDNF to mBDNF in the hippocampus.

Abstract

Some studies have indicated that ketamine has a rapid antidepressant effects, but the underlying molecular mechanism is still unclear. Researchers have found that mature brain-derived neurotrophic factor (mBDNF) and its precursor proBDNF are related to depression; they elicit opposite effects on cellular functions. It is clear that tissue plasminogen activator (tPA) is a key regulatory element in the conversion of proBDNF to mBDNF. The chronic unpredicted mild stress (CUMS) procedure is a classical and reliable method to establish the model of depression. This study found that sucrose preference and locomotor activity were both reduced in CUMS-treated rats while were increased in those who were injected with ketamine. The hippocampal proBDNF/mBDNF ratio was downregulated after ketamine treatment in those rats, together with an increased level of tPA in the hippocampus. However, tPA activity was unaltered after ketamine intraperitoneal injection. Intrahippocampal injection of active plasminogen activator inhibitor-1 (inhibitor of tPA) before ketamine treatment reversed the antidepressant effects and upregulated the proBDNF/mBDNF ratio. The results of this study suggest that the antidepressant action induced by ketamine may be related to tPA-mediated conversion of proBDNF to mBDNF in the hippocampus.

Comparable studies

Other preclinical and animal studies on ketamine for depression, most cited first.

Study Year Design Participants
Psychedelics, but Not Ketamine, Produce Persistent Antidepressant-like Effects in a Rodent Experimental System for the Study of Depression Rats 2020 Preclinical study
A Single Subanesthetic Dose of Ketamine Relieves Depression-like Behaviors Induced by Neuropathic Pain in Rats Rats with spared nerve injury (neuropathic pain model), sham-operated rats, and control... 2011 Animal experimental study
Comparison of (R)-ketamine and lanicemine on depression-like phenotype and abnormal composition of gut microbiota in a social defeat stress model Susceptible mice after chronic social defeat stress 2017 Preclinical animal study
Comparison of R-ketamine and rapastinel antidepressant effects in the social defeat stress model of depression Susceptible mice in the social defeat stress model 2016 Animal experimental study
Ketamine and its metabolite, (2R,6R)-HNK, restore hippocampal LTP and long-term spatial memory in the Wistar-Kyoto rat model of depression Wistar-Kyoto (WKY) rats and Wistar control rats 2020 Preclinical study

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