Mirtazapine increases glial cell line-derived neurotrophic factor production through lysophosphatidic acid 1 receptor-mediated extracellular signal-regulated kinase signaling in astrocytes

Hisaoka-Nakashima, Kazue; Taki, Sayaka; Watanabe, Shintaro; Nakamura, Yoki; Nakata, Yoshihiro; Morioka, Norimitsu

doi:10.1016/j.ejphar.2019.172539

Cited by 20 publications

(14 citation statements)

References 33 publications

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“…Furthermore, we confirmed the involvement of MT-1/2 in mirtazapine-induced neuroprotection by adding an anti-MT-1/2 antibody to Mir-NCM-ACM demonstrating that the MT-absorbed Mir-NCM-ACM failed to exert neuroprotective effects against 6-OHDA neurotoxicity. In addition to our results, it has been reported that mirtazapine increases the production of glial cell line-derived neurotrophic factor through lysophosphatidic acid 1 (LPA1) receptor in astrocytes 25 . However, in our experiments, ACM from mirtazapine-treated astrocytes could not protect dopaminergic neuron against 6-OHDA toxicity.…”

Section: Discussionsupporting

confidence: 84%

Mirtazapine exerts astrocyte-mediated dopaminergic neuroprotection

Kikuoka

Miyazaki

Kubota

et al. 2020

Sci Rep

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Mirtazapine, a noradrenergic and specific serotonergic antidepressant (NaSSA), is known to activate serotonin (5-HT) 1A receptor. Our recent study demonstrated that stimulation of astrocytic 5-HT1A receptors promoted astrocyte proliferation and upregulated antioxidative property in astrocytes to protect dopaminergic neurons against oxidative stress. Here, we evaluated the neuroprotective effects of mirtazapine against dopaminergic neurodegeneration in models of Parkinson’s disease (PD). Mirtazapine administration attenuated the loss of dopaminergic neurons in the substantia nigra and increased the expression of the antioxidative molecule metallothionein (MT) in the striatal astrocytes of 6-hydroxydopamine (6-OHDA)-injected parkinsonian mice via 5-HT1A receptors. Mirtazapine protected dopaminergic neurons against 6-OHDA-induced neurotoxicity in mesencephalic neuron and striatal astrocyte cocultures, but not in enriched neuronal cultures. Mirtazapine-treated neuron-conditioned medium (Mir-NCM) induced astrocyte proliferation and upregulated MT expression via 5-HT1A receptors on astrocytes. Furthermore, treatment with medium from Mir-NCM-treated astrocytes protected dopaminergic neurons against 6-OHDA neurotoxicity, and these effects were attenuated by treatment with a MT-1/2-specific antibody or 5-HT1A antagonist. Our study suggests that mirtazapine could be an effective disease-modifying drug for PD and highlights that astrocytic 5-HT1A receptors may be a novel target for the treatment of PD.

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Section: Discussionsupporting

confidence: 84%

Mirtazapine exerts astrocyte-mediated dopaminergic neuroprotection

Kikuoka

Miyazaki

Kubota

et al. 2020

Sci Rep

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“…Antidepressants have been shown to interact with the LPA 1 receptor and activate downstream intracellular signaling (Hisaoka‐Nakashima et al., 2019; Kajitani et al., 2016; Olianas et al., 2016). Tricyclic antidepressant (amitriptyline, imipramine, and desipramine), tetracyclic antidepressant (mianserin), selective serotonin reuptake inhibitors (SSRI; fluoxetine, and paroxetine), serotonin noradrenaline reuptake inhibitors (SNRI; duloxetine), or noradrenergic and specific serotonergic antidepressant (NaSSA; mirtazapine), significantly increased TSP‐1 mRNA and protein expression in astrocytes (Figure 8a–c).…”

Section: Resultsmentioning

confidence: 99%

“…An average of 10–12 pups per experiment were used. Primary cultured astrocytes were prepared as described previously (Hisaoka‐Nakashima et al., 2019; Kajitani et al., 2015). Neonatal rat pups (1 day old) underwent hypothermia on an ice‐cold glass plate and were then decapitated with a pair of scissors (AVMA, 2020) (Leary et al 2020).…”

Section: Methodsmentioning

confidence: 99%

Lysophosphatidic acid induces thrombospondin‐1 production in primary cultured rat cortical astrocytes

Hisaoka-Nakashima

Yokoe

Watanabe

et al. 2020

Journal of Neurochemistry

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Lysophosphatidic acid (LPA), a brain membrane‐derived lipid mediator, plays important roles including neural development, function, and behavior. In the present study, the effects of LPA on astrocyte‐derived synaptogenesis factor thrombospondins (TSPs) production were examined by real‐time PCR and western blotting, and the mechanism underlying this event was examined by pharmacological approaches in primary cultured rat cortical astrocytes. Treatment of astrocytes with LPA increased TSP‐1 mRNA, and TSP‐2 mRNA, but not TSP‐4 mRNA expression. TSP‐1 protein expression and release were also increased by LPA. LPA‐induced TSP‐1 production were inhibited by AM966 a LPA1 receptor antagonist, and Ki16425, LPA1/3 receptors antagonist, but not by H2L5146303, LPA2 receptor antagonist. Pertussis toxin, Gi/o inhibitor, but not YM‐254890, Gq inhibitor, and NF499, Gs inhibitor, inhibited LPA‐induced TSP‐1 production, indicating that LPA increases TSP‐1 production through Gi/o‐coupled LPA1 and LPA3 receptors. LPA treatment increased phosphorylation of extracellular signal‐regulated kinase (ERK), p38 mitogen‐activated protein kinase (MAPK), and c‐Jun N‐terminal kinase (JNK). LPA‐induced TSP‐1 mRNA expression was inhibited by U0126, MAPK/ERK kinase (MEK) inhibitor, but not SB202190, p38 MAPK inhibitor, or SP600125, JNK inhibitor. However, LPA‐induced TSP‐1 protein expression was diminished with inhibition of all three MAPKs, indicating that these signaling molecules are involved in TSP‐1 protein production. Treatment with antidepressants, which bind to astrocytic LPA1 receptors, increased TSP‐1 mRNA and protein production. The current findings show that LPA/LPA1/3 receptors signaling increases TSP‐1 production in astrocytes, which could be important in the pathogenesis of affective disorders and could potentially be a target for the treatment of affective disorders.

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“…Decreased astrocytes and downregulated AQP4 expression have been reported in various animal models of depression (47, 48, 123, 124, 130) (Table 1), supporting dysfunctional glymphatic transport in depression. Effective antidepressant therapy, such as fluoxetine (47, 124, 125), escitalopram (48), mirtazapine (126), ketamine (127,128), and repetitive high-frequency transcranial magnetic stimulation (TMS) (129) could benefit the functioning of both astrocytes and AQP4, and hence alleviate depressive-like behaviors. Additionally, the synergistic agents of antidepressantlithium-can attenuate the reduction of AQP4 and disruption of the neurovascular unit in the hippocampus of CUMS rats (130), resulting in a functioning glymphatic system.…”

Section: Abnormalities Of Glymphatic Flow Astrocytes and Aqp4 In Depressionmentioning

confidence: 99%

Glymphatic Dysfunction: A Bridge Between Sleep Disturbance and Mood Disorders

Yan

Qiu

et al. 2021

Front. Psychiatry

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Mounting evidence demonstrates a close relationship between sleep disturbance and mood disorders, including major depression disorder (MDD) and bipolar disorder (BD). According to the classical two-process model of sleep regulation, circadian rhythms driven by the light–dark cycle, and sleep homeostasis modulated by the sleep–wake cycle are disrupted in mood disorders. However, the exact mechanism of interaction between sleep and mood disorders remains unclear. Recent discovery of the glymphatic system and its dynamic fluctuation with sleep provide a plausible explanation. The diurnal variation of the glymphatic circulation is dependent on the astrocytic activity and polarization of water channel protein aquaporin-4 (AQP4). Both animal and human studies have reported suppressed glymphatic transport, abnormal astrocytes, and depolarized AQP4 in mood disorders. In this study, the “glymphatic dysfunction” hypothesis which suggests that the dysfunctional glymphatic pathway serves as a bridge between sleep disturbance and mood disorders is proposed.

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Mirtazapine increases glial cell line-derived neurotrophic factor production through lysophosphatidic acid 1 receptor-mediated extracellular signal-regulated kinase signaling in astrocytes

Cited by 20 publications

References 33 publications

Mirtazapine exerts astrocyte-mediated dopaminergic neuroprotection

Mirtazapine exerts astrocyte-mediated dopaminergic neuroprotection

Lysophosphatidic acid induces thrombospondin‐1 production in primary cultured rat cortical astrocytes

Glymphatic Dysfunction: A Bridge Between Sleep Disturbance and Mood Disorders

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