Anti-Depressant Fluoxetine Reveals its Therapeutic Effect Via Astrocytes

Kinoshita, Manao; Hirayama, Yuri; Fujishita, Kayoko; Shibata, Keisuke; Shinozaki, Youichi; Shigetomi, Eiji; Takeda, Akiko; Le, Ha Pham Ngoc; Hayashi, Hideaki; Hiasa, Miki; Moriyama, Yoshinori; Ikenaka, Kazuhiro; Tanaka, Kenji F.; Koizumi, Schuichi

doi:10.1016/j.ebiom.2018.05.036

Cited by 94 publications

(62 citation statements)

References 71 publications

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“…Therapeutic effects of antidepressants on MDD by modulation of astrocytic function (such as producing BDNF and GDNF) have been reported [36–39]. Though animal and clinical studies on MDD showed increased BDNF with n-3 PUFA treatment [40–42], the relevant cell types were not delineated.…”

Section: Resultsmentioning

confidence: 99%

N-3 polyunsaturated fatty acids promote astrocyte differentiation and neurotrophin production independent of cAMP in patient-derived neural stem cells

Wang

Sheridan

et al. 2020

Preprint

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30Evidence from epidemiological and laboratory studies, as well as randomized placebo-controlled 31 trials, suggests supplementation with n-3 polyunsaturated fatty acids (PUFAs) may be efficacious 32 for treatment of major depressive disorder (MDD). The mechanisms underlying n-3 PUFAs 33 potential therapeutic properties remain unknown. There are suggestions in the literature that glial 34 hypofunction is associated with depressive symptoms and that antidepressants may normalize 35 glial function. In this study, iPSC-derived neuronal stem cell lines were generated from 36 individuals with MDD. Astrocytes differentiated from patient-derived neuronal stem cells 37 (iNSCs) were verified by GFAP. Cells were treated with eicosapentaenoic acid (EPA), 38 docosahexaenoic acid (DHA) and stearic acid (SA). During astrocyte differentiation, we found 39 that n-3 PUFAs increased GFAP expression and GFAP positive cell formation. BDNF and 40 GDNF production were increased in the astrocytes derived from patients subsequent to n-3 41 PUFA treatment. Stearic Acid (SA) treatment did not have this effect. CREB activity 42 (phosphorylated CREB) was also increased by DHA and EPA but not by SA. Furthermore, when 43 these astrocytes were treated with n-3 PUFAs, the cAMP antagonist, RP-cAMPs did not block n-44 3 PUFA CREB activation. However, the CREB specific inhibitor (666-15) diminished BDNF 45 and GDNF production induced by n-3 PUFA, suggesting CREB dependence. Together, these 46 results suggested that n-3 PUFAs facilitate astrocyte differentiation, and may mimic effects of 47 some antidepressants by increasing production of neurotrophic factors. The CREB-dependence 48 and cAMP independence of this process suggests a manner in which n-3 PUFA could augment 49 antidepressant effects. These data also suggest a role for astrocytes in both MDD and 50 antidepressant action. 51 52 53Major depressive disorder (MDD) is the most common psychiatric disorder, with almost 54 one in six individuals experiencing at least one depressive episode at some point in their lifetime. 55It is currently the leading cause of disability worldwide [1, 2]. While effective treatments exist, 56 about one third of patients treated with antidepressants do not reach symptomatic remission [3, 57 4]. While some of these non-remitters may respond to ketamine or other rescue strategies, 58 additional therapeutic options are needed. 59Brain regions and even cell-types contributing to MDD are not well established [4]. 60Evidence from clinical, preclinical and post-mortem studies suggests that dysfunction and 61 degeneration of astrocytes may be one of potential candidates, and astrocytes may also represent 62 a potential therapeutic target for MDD [5][6][7][8]. Antidepressants, including SSRIs and ketamine, 63 increase brain-derived neurotrophic factor (BDNF) and glial cell-derived neurotrophic factor 64 (GDNF) expression in primary cultured animal astrocytes [9][10][11]. Substantial evidence suggested 65 that astrocytes might be the main resource of antidepressant...

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Section: Resultsmentioning

confidence: 99%

N-3 polyunsaturated fatty acids promote astrocyte differentiation and neurotrophin production independent of cAMP in patient-derived neural stem cells

Wang

Sheridan

et al. 2020

Preprint

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“…Conventional KO and conditioned astrocytic KO of the calcium homeostasis modulator 2 channel (Calhm2) initiated depression-like behaviors in mice (TST and FST), indicating that this channel is the exit pathway for the release of ATP (Jun et al, 2018). In partial disagreement with these findings, the effect of the antidepressant drug fluoxetine has been shown to increase ATP exocytosis (Kinoshita et al, 2018). In consequence, the authors of this latter study concluded that the astrocytic release of ATP involved in depression operates by vesicular exocytosis rather than by Calhm2 opening.…”

Section: Inhibited Astrocytic Atp Release In the Prefrontal Cortex Anmentioning

confidence: 99%

Pathological ATPergic Signaling in Major Depression and Bipolar Disorder

Illéš

Verkhratsky

Tang

2020

Front. Mol. Neurosci.

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The mood disorders, major depression (MD) and bipolar disorder (BD), have a high lifetime prevalence in the human population and accordingly generate huge costs for health care. Efficient, rapidly acting, and side-effect-free pharmaceuticals are hitherto not available, and therefore, the identification of new therapeutic targets is an imperative task for (pre)clinical research. Such a target may be the purinergic P2X7 receptor (P2X7R), which is localized in the central nervous system (CNS) at microglial and neuroglial cells mediating neuroinflammation. MD and BD are due to neuroinflammation caused in the first line by the release of the pro-inflammatory cytokine interleukin-1β (IL-1β) from the microglia. IL-1β in turn induces the secretion of corticotropin-releasing hormone (CRH) and in consequence the secretion of adrenocorticotropic hormone (ACTH) and cortisol, which together with a plethora of further cytokines/chemokines lead to mood disorders. A number of biochemical/molecular biological measurements including the use of P2X7R-or IL-1β-deficient mice confirmed this chain of events. More recent studies showed that a decrease in the astrocytic release of ATP in the prefrontal cortex and hippocampus is a major cause of mood disorders. It is an attractive hypothesis that compensatory increases in P2X7Rs in these areas of the brain are the immediate actuators of MD and BD. Hence, blood-brain barrier-permeable P2X7R antagonists may be promising therapeutic tools to improve depressive disorders in humans.

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“…Additional mechanisms, including the possible involvement of A2A receptors in metabolism and neuroinflammation and the role of neurochemical mediators of antidepressant responses, have been considered [22]. For example, it has been shown that fluoxetine-induced upregulation of the Brain-Derived Neurotrophic Factor (BDNF), involved in depression pathophysiology [49], may be mediated by both P1 and P2 receptor signaling [50].…”

Section: Adenosine and Depressionmentioning

confidence: 99%

Purinergic Signaling and Related Biomarkers in Depression

et al. 2020

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It is established that purinergic signaling can shape a wide range of physiological functions, including neurotransmission and neuromodulation. The purinergic system may play a role in the pathophysiology of mood disorders, influencing neurotransmitter systems and hormonal pathways of the hypothalamic-pituitary-adrenal axis. Treatment with mood stabilizers and antidepressants can lead to changes in purinergic signaling. In this overview, we describe the biological background on the possible link between the purinergic system and depression, possibly involving changes in adenosine- and ATP-mediated signaling at P1 and P2 receptors, respectively. Furthermore, evidence on the possible antidepressive effects of non-selective adenosine antagonist caffeine and other purinergic modulators is reviewed. In particular, A2A and P2X7 receptors have been identified as potential targets for depression treatment. Preclinical studies highlight that both selective A2A and P2X7 antagonists may have antidepressant effects and potentiate responses to antidepressant treatments. Consistently, recent studies feature the possible role of the purinergic system peripheral metabolites as possible biomarkers of depression. In particular, variations of serum uric acid, as the end product of purinergic metabolism, have been found in depression. Although several open questions remain, the purinergic system represents a promising research area for insights into the molecular basis of depression.

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Anti-Depressant Fluoxetine Reveals its Therapeutic Effect Via Astrocytes

Cited by 94 publications

References 71 publications

N-3 polyunsaturated fatty acids promote astrocyte differentiation and neurotrophin production independent of cAMP in patient-derived neural stem cells

N-3 polyunsaturated fatty acids promote astrocyte differentiation and neurotrophin production independent of cAMP in patient-derived neural stem cells

Pathological ATPergic Signaling in Major Depression and Bipolar Disorder

Purinergic Signaling and Related Biomarkers in Depression

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