Hippocampal PPARα is a novel therapeutic target for depression and mediates the antidepressant actions of fluoxetine in mice

Song, Lu; Wang, Hao; Wang, Yingjie; Wang, Jinliang; Zhu, Qing; Wu, Feng; Zhang, Wei; Jiang, Bo

doi:10.1111/bph.14346

Cited by 59 publications

(41 citation statements)

References 67 publications

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“…This action also appears to be mediated by enhancing the hippocampal expression of BDNF signaling pathway via the PPAR-α-mediated activation of CREB [88]. Consistent with these findings, in a chronic stress-induced mouse model of depression, PPAR-α expression is decreased in the hippocampus, which in turn results in reduced hippocampal BDNF expression [89]. Conversely, genetic overexpression of PPAR-α induces antidepressant effects by a CREB-mediated biosynthesis of BDNF.…”

Section: Mood Disorderssupporting

confidence: 58%

“…Conversely, genetic overexpression of PPAR-α induces antidepressant effects by a CREB-mediated biosynthesis of BDNF. Both genetic or pharmacological inhibition of PPAR-α blocks the anti-depressive effects of fluoxetine, thereby suggesting its involvement in the molecular mechanisms of antidepressant drug action [89].…”

Section: Mood Disordersmentioning

confidence: 99%

“…Collectively, these studies involving PPAR-α and γ in the neuropathophysiology of psychiatric disorders have opened up new opportunities for the development of new therapeutics, which represent a novel emerging field of neuropsychopharmacology [18,66,89,122].…”

Section: Neurodevelopmental Disordersmentioning

confidence: 99%

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Is There a Future for PPARs in the Treatment of Neuropsychiatric Disorders?

Tufano

Pinna

2020

Molecules

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Recently, peroxisome proliferator-activated receptor (PPAR)-α and γ isoforms have been gaining consistent interest in neuropathology and treatment of neuropsychiatric disorders. Several studies have provided evidence that either the receptor expression or the levels of their endogenously-produced modulators are downregulated in several neurological and psychiatric disorders and in their respective animal models. Remarkably, administration of these endogenous or synthetic ligands improves mood and cognition, suggesting that PPARs may offer a significant pharmacological target to improve several neuropathologies. Furthermore, various neurological and psychiatric disorders reflect sustained levels of systemic inflammation. Hence, the strategy of targeting PPARs for their anti-inflammatory role to improve these disorders is attracting attention. Traditionally, classical antidepressants fail to be effective, specifically in patients with inflammation. Non-steroidal anti-inflammatory drugs exert potent antidepressant effects by acting along with PPARs, thereby strongly substantiating the involvement of these receptors in the mechanisms that lead to development of several neuropathologies. We reviewed running findings in support of a role for PPARs in the treatment of neurological diseases, including Alzheimer’s disease or psychiatric disorders, such as major depression. We discuss the opportunity of targeting PPARs as a future pharmacological approach to decrease neuropsychiatric symptoms at the same time that PPAR ligands resolve neuroinflammatory processes.

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Section: Mood Disorderssupporting

confidence: 58%

Section: Mood Disordersmentioning

confidence: 99%

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Is There a Future for PPARs in the Treatment of Neuropsychiatric Disorders?

Tufano

Pinna

2020

Molecules

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“…The SSRIs and SNRIs are designed to speci cally impede the activity of neurotransmitter transporters. However, mounting evidence has suggested the existence of various additional targets for these neurotransmitter re-uptake inhibitors, which either support the therapeutic effect, or on the contrary trigger adverse events [24][25][26][27]. Examples include the protection of paroxetine against dyskinesia in Huntingtin mutant mice and nigrostriatal neurodegeneration in Parkinson's disease mouse model [28,29], and the venlafaxine-mediated improvement of cognitive impairment and depressive behavior in multiple sclerosis mouse model [30].…”

Section: Discussionmentioning

confidence: 99%

Differential and paradoxical roles of new-generation antidepressants in primary astrocytic inflammation

Liu

Peng

et al. 2020

Preprint

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Background: Selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs) are commonly used new-generation drugs for depression. Depressive symptoms are thought to be closely related to neuroinflammation. In this study, we used up-to-date protocols of culture and stimulation and aimed to understand how astrocytes respond to the antidepressants. Methods: Primary astrocytes were isolated and cultured using neurobasal-based serum free medium. The cells were treated with a cytokine mixture comprising complement component 1q, tumor necrosis factor α and interleukin 1α with or without pretreatments of antidepressants. Cell viability, phenotypes, inflammatory responses and the underlying mechanisms were analyzed. Results: All the SSRIs, including paroxetine, fluoxetine, sertraline, citalopram, and fluvoxamine, show a visible cytotoxicity within the range of applied doses, and a paradoxical effect on astrocytic inflammatory responses as manifested by the promotion of inducible nitric oxide synthase (iNOS) and/or nitric oxide (NO) and the inhibition of interleukin 6 (IL-6) and/or interleukin 1β (IL-1β). The SNRI venlafaxine was the least toxic to astrocytes and inhibited the production of IL-6 and IL-1β but with no impact on iNOS and NO. All the drugs had no regulation on the polarization of astrocytic A1 and A2 types. Mechanisms associated with the antidepressants in astrocytic inflammation route via inhibition of JNK1 activation and STAT3 basal activity. Conclusions: The study demonstrated that the antidepressants possess differential cytotoxicity to astrocytes and function differently, also paradoxically for the SSRIs, to astrocytic inflammation. Our results provide novel pieces into understanding the differential efficacy and tolerability of the antidepressants in treating patients in the context of astrocytes.

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“…Apocynin (5 mg/kg/day, Calbiochem, Gibbstown, NJ) was administrated orally, dissolved in drink water [25]. SSRI (10 mL/kg fluoxetine dissolved) was injected intraperitoneally, dissolved in 0.9% saline (0.9% NaCl, pH 7.4) accordingly [26] In vitro assays, serotonin (5 μM) and SSRI (10 μM fluoxetine hydrochloride, Sigma-Aldrich) were dissolved in dimethyl sulfoxide (DMSO) according to previous study [27,28]. Then, the optical density (OD) value (450 nm) was determined by an enzyme-linked immunosorbent assay plate reader (Bioreader).…”

Section: Animalsmentioning

confidence: 99%

Depression Accelerates Tumor Cell Proliferation Via Regulating Serotonin/miR-144 Axis in NSCLC Mice

Xu¹,

Li²,

Zhu³

et al. 2020

Act Scie Pharma

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Non-small cell lung cancer is known as a malignant tumor with low survival rate and poor prognosis. Depression affects various diseases. However, the effect of depression on the progression of NSCLC remains unclear. In our current study, chronic mild stress (CMS) mice was used as depression animal model. Depression prompted the tumor progression in vivo analysis, including increasing tumor indexes and reducing survival rate. Serotonin secretion was observed to be remarkable elevation in both serum and tumor tissue, which was positively related with tumor progression. In vitro assays, serotonin promoted the proliferation of A549 cells. Additionally, we observed that miR-144 expression was significantly downregulated in serotonin stimulated group. Further loss-of-and gain-of-function assays verified that miR-144 was the downstream factor of serotonin underlying the condition of CMS. Taken together, our research indicated that CMS-induced serotonin secretion accelerates NSCLC proliferation via inhibiting miR-144 expression, suggesting the potential therapeutic direction in NSCLC patients.

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Hippocampal PPARα is a novel therapeutic target for depression and mediates the antidepressant actions of fluoxetine in mice

Abstract: Hippocampal PPARα is a potential novel antidepressant target that mediates the antidepressant actions of fluoxetine in mice.

Cited by 59 publications

References 67 publications

Is There a Future for PPARs in the Treatment of Neuropsychiatric Disorders?

Is There a Future for PPARs in the Treatment of Neuropsychiatric Disorders?

Differential and paradoxical roles of new-generation antidepressants in primary astrocytic inflammation

Depression Accelerates Tumor Cell Proliferation Via Regulating Serotonin/miR-144 Axis in NSCLC Mice

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