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Antidepressant-like effects of fenofibrate in mice via the hippocampal brain-derived neurotrophic factor signalling pathway.

ABSTRACT: BACKGROUND AND PURPOSE:Depression is a neuropsychiatric disorder accompanied by a decrease in the brain-derived neurotrophic factor (BDNF) signalling cascade in the hippocampus. Fenofibrate is a selective agonist of PPAR-?. In this study, we investigated the antidepressant-like effects of fenofibrate in C57BL/6J mice. EXPERIMENTAL APPROACH:The antidepressant-like effects of fenofibrate were first identified in the forced swim test (FST) and tail suspension test (TST), and then assessed in the chronic social defeat stress (CSDS) model. The changes in the hippocampal BDNF signalling pathway and adult hippocampal neurogenesis after CSDS and fenofibrate treatment were further investigated. A PPAR-? inhibitor, cannabinoid system inhibitors and BDNF signalling inhibitors were also used to determine the antidepressant mechanisms of fenofibrate. KEY RESULTS:Fenofibrate administration exhibited antidepressant-like effects in the FST and TST without affecting the locomotor activity of mice. Chronic fenofibrate treatment also prevented the depressive-like symptoms induced by CSDS. Moreover, fenofibrate restored the CSDS-induced decrease in the hippocampal BDNF signalling cascade and adult hippocampal neurogenesis. The antidepressant-like effects of fenofibrate could be blocked by a PPAR-? inhibitor and BDNF signalling inhibitors. CONCLUSIONS AND IMPLICATIONS:Taken together, these results suggest that fenofibrate has antidepressant-like effects mediated through the promotion of the hippocampal BDNF signalling cascade.

SUBMITTER: Jiang B

PROVIDER: S-EPMC5192965 | biostudies-literature | 2017 Jan

REPOSITORIES: biostudies-literature

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Antidepressant-like effects of fenofibrate in mice via the hippocampal brain-derived neurotrophic factor signalling pathway.

Jiang Bo B Wang Ying-Jie YJ Wang Hao H Song Lu L Huang Chao C Zhu Qing Q Wu Feng F Zhang Wei W

British journal of pharmacology 20161209 2

<h4>Background and purpose</h4>Depression is a neuropsychiatric disorder accompanied by a decrease in the brain-derived neurotrophic factor (BDNF) signalling cascade in the hippocampus. Fenofibrate is a selective agonist of PPAR-α. In this study, we investigated the antidepressant-like effects of fenofibrate in C57BL/6J mice.<h4>Experimental approach</h4>The antidepressant-like effects of fenofibrate were first identified in the forced swim test (FST) and tail suspension test (TST), and then ass ...[more]

PMID: 27861729

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Project description:Despite significant advances in the understanding of the therapeutic activity of antidepressant drugs, treatment-resistant depression is a public health issue prompting research to identify new therapeutic strategies. Evidence strongly suggests that nutrition might exert a significant impact on the onset, the duration and the severity of major depression. Accordingly, preclinical and clinical investigations demonstrated the beneficial effects of omega-3 fatty acids in anxiety and mood disorders. Although the neurobiological substrates of its action remain poorly documented, basic research has shown that omega-3 increases brain-derived neurotrophic factor (BDNF) levels in brain regions associated with depression, as antidepressant drugs do. In contrast, low BDNF levels and hippocampal atrophy were observed in animal models of depression. In this context, the present study compared the effects of long-lasting fish oil-enriched diet, an important source of omega-3 fatty acids, between heterozygous BDNF+/- mice and their wild-type littermates. Our results demonstrated lower activation of Erk in BDNF+/- mice whereas this deficit was rescued by fish oil-enriched diet. In parallel, BDNF+/- mice displayed elevated hippocampal extracellular 5-HT levels in relation with a local decreased serotonin transporter protein level. Fish oil-enriched diet restored normal serotonergic tone by increasing the protein levels of serotonin transporter. At the cellular level, fish oil-enriched diet increased the pool of immature neurons in the dentate gyrus of BDNF+/- mice and the latter observations coincide with its ability to promote anxiolytic- and antidepressant-like response in these mutants. Collectively, our results demonstrate that the beneficial effects of long-term exposure to fish oil-enriched diet in behavioral paradigms known to recapitulate diverse abnormalities related to the depressive state specifically in mice with a partial loss of BDNF. These findings contrast with the mechanism of action of currently available antidepressant drugs for which the full manifestation of their therapeutic activity depends on the enhancement of serotoninergic and BDNF signaling. Further studies are warranted to determine whether fish oil supplementation could be used as an add-on strategy to conventional pharmacological interventions in treatment-resistant patients and relevant animal models.

Dataset Information

Antidepressant-like effects of fenofibrate in mice via the hippocampal brain-derived neurotrophic factor signalling pathway.

Publications

Antidepressant-like effects of fenofibrate in mice via the hippocampal brain-derived neurotrophic factor signalling pathway.

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