Tricyclic Antidepressant Amitriptyline-induced Glial Cell Line-derived Neurotrophic Factor Production Involves Pertussis Toxin-sensitive Gαi/o Activation in Astroglial Cells

Hisaoka-Nakashima, Kazue; Miyano, Kanako; Matsumoto, Chieko; Kajitani, Naoto; Abe, Hiromi; Okada‐Tsuchioka, Mami; Yokoyama, Akinobu; Uezono, Yasuhito; Morioka, Norimitsu; Nakata, Yoshihiro; Takebayashi, Minoru

doi:10.1074/jbc.m114.622415

Cited by 37 publications

(37 citation statements)

References 62 publications

(91 reference statements)

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“…One of these drugs could be the tricyclic antidepressant amitriptyline, as it was shown to decrease the release of BDNF [91], and, at the same time, increase that of GDNF at least in glia [92]. If one considers the picture emerged from a more precise dissection of the nociceptive circuitries in the substantia gelatinosa of the spinal cord (Figure2), amitriptyline has the potential to target at the same time a pro-(BDNF) and an antinociceptive (GDNF) factor at this very important relay station.…”

Section: An Interesting Option For Developing New Drugs Is Thus Targementioning

confidence: 99%

Targeting the glial-derived neurotrophic factor and related molecules for controlling normal and pathologic pain

Merighi

2015

Expert Opinion on Therapeutic Targets

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Introduction: GDNF and its family of ligands (GFLs) have several functions in the nervous system. As a survival factor for dopaminergic neurons, GDNF was used in clinical trials for Parkinson's disease. However, GFLs their receptors are potential targets for new pain-controlling drugs. Such a potential should not be underestimated because molecules with analgesic activities in rodents mostly failed to be effective in translational studies. Areas covered:The circuitry, molecular and cellular mechanisms by which GFLs control nociception, their intervention in inflammatory and neuropathic pain, the problems related to effective GDNF delivery to the brain, the possibility to target the GFL receptor complex rather than its ligands, also by the use of non-peptidyl agonists, are discussed. Expert opinion:In nociceptive pathways, an ideal drug should either: i. Target the release of endogenous GFLs from large dense-cored vesicles (LGVs) by acting e.g. onto the phosphatidylinositol-3-phosphate [PtdIns(3)P] pool, which is sensitive to Ca 2+ modulation; ii. Target the GFL receptor complex. Besides to XIB403, a thiol molecule that enhances GFRα family receptor signaling, existing drugs such as retinoic acid and amitriptyline should be considered for effective targeting of GDNF, at least in neuropathic pain. The approach of pain modeling in experimental animals is discussed.

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Section: An Interesting Option For Developing New Drugs Is Thus Targementioning

confidence: 99%

Targeting the glial-derived neurotrophic factor and related molecules for controlling normal and pathologic pain

Merighi

2015

Expert Opinion on Therapeutic Targets

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“…12) Thus, although these findings demonstrate that the Gi/o protein is a key molecule regulating GDNF expression, it is not known whether direct activation of Gi/o protein could induce GDNF expression, and what mechanism might be involved after Gi/o protein activation.…”

Section: )mentioning

confidence: 80%

“…The concentrations of inhibitors (PTX, U0126, SU5402, and PD173074) used in this study selectively inhibit its target, and no other kinases, in rat primary cultured astrocytes. 12,19) U0126, SU5402, and PD173074 were dissolved in dimethyl sulfoxide (DMSO). The final concentration of DMSO was adjusted to 0.1% for drug treatment experiments.…”

Section: Methodsmentioning

confidence: 99%

Pharmacological Activation Gi/o Protein Increases Glial Cell Line-Derived Neurotrophic Factor Production through Fibroblast Growth Factor Receptor and Extracellular Signal-Regulated Kinase Pathway in Primary Cultured Rat Cortical Astrocytes

Hisaoka-Nakashima

Matsumoto

Azuma

et al. 2017

Biological & Pharmaceutical Bulletin

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A significant reduction of glial cell line-derived neurotrophic factor (GDNF) has been identified in the pathophysiology of neurodegenerative and neuropsychiatric disorders. Thus, clarification of the mechanism of GDNF production, and modulating brain GDNF levels could be a novel therapeutic approach. A previous study demonstrated that antidepressant amitriptyline-induced GDNF production was significantly inhibited by pertussis toxin (PTX), a Gi/o protein inhibitor in astrocytes, the main source of GDNF in the brain. However, it is not known whether direct activation of Gi/o protein might induce GDNF expression, and what mechanisms might be involved after Gi/o protein activation. The current study investigated Gi/o proteininitiated GDNF production in rat cortical astrocytes using activators that directly activate Gi/o protein, mastoparan and compound48/80. Treatment of astrocytes with either mastoparan or compound48/80 increased GDNF mRNA expression at 3 and 6 h, and GDNF protein release at 24 h. Treatment of astrocyte with either mastoparan or compound48/80 increased brain-derived neurotrophic factor (BDNF) mRNA expression as well as GDNF. Mastoparan and compound48/80-induced GDNF mRNA expression were significantly inhibited by not only PTX, but also fibroblast growth factor receptor (FGFR) inhibitors, and mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) kinase (MEK) inhibitor. In fact, both FGFR substrate2α (FRS2α) and ERK phosphorylation were increased by treatment with either mastoparan or compound48/80, and these were significantly blocked by PTX. Thus, direct, receptor-independent Gi/o protein activation increases GDNF production through FGFR/ERK signaling pathway. The current results indicate a critical role of Gi/o signaling in the regulation of GDNF expression in astrocytes.Key words astrocyte; Gi/o protein; glial cell line-derived neurotrophic factor; brain-derived neurotrophic factor; neurodegenerative disorder; neuropsychiatric disorder Glial cell line-derived neurotrophic factor (GDNF) was originally identified in conditioned medium of a glial cell line as an index of viability of midbrain tyrosine hydroxylasepositive dopaminergic neurons.

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“…Distinct classes of antidepressants, such as tricyclic, tetracyclic antidepressants, and selective 5‐HT reuptake inhibitor (SSRI), increase GDNF production in rat C6 glial cells (C6 cells) and primary cultured rat astrocytes (primary astrocytes), but not in primary neurons . In addition, the antidepressant amitriptyline increased GDNF production via Gα i/o ‐coupled lysophosphatidic acid receptor 1 (LPAR1)/matrix metalloproteinase‐9 (MMP‐9)/fibroblast growth factor (FGFR)/ERK cascade . However, the precise intracellular signaling pathway between LPAR1/Gα i/o and MMP‐9 is yet unknown.…”

Section: Introductionmentioning

confidence: 99%

“…7,8 In addition, the antidepressant amitriptyline increased GDNF production via Gα i/o -coupled lysophosphatidic acid receptor 1 (LPAR1)/matrix metalloproteinase-9 (MMP-9)/fibroblast growth factor (FGFR)/ERK cascade. 7,[9][10][11][12] However, the precise intracellular signaling pathway between LPAR1/Gα i/o and MMP-9 is yet unknown. It has been reported that G proteins regulate MMPs via intracellular signaling molecules, such as Src family tyrosine kinase, calcium (Ca 2+ ) ions, and protein kinase C (PKC).…”

Section: Introductionmentioning

confidence: 99%

Antidepressant amitriptyline‐induced matrix metalloproteinase‐9 activation is mediated by Src family tyrosine kinase, which leads to glial cell line‐derived neurotrophic factor mRNA expression in rat astroglial cells

Abe

Kajitani

Okada‐Tsuchioka

et al. 2019

Neuropsychopharm Rep

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Background Astrocytes have been implicated in the pathophysiology of mood disorders and in the mechanism of the pharmacological effects of antidepressant drugs by the production of neurotrophic/growth factors. Previous studies have identified astrocyte‐expressed Gαi/o‐coupled lysophosphatidic acid receptor 1 (LPAR1), as being involved in antidepressant‐induced production of glial cell line‐derived neurotrophic factor (GDNF) and matrix metalloproteinase‐9 (MMP‐9) activation, an important step in the production of GNDF. However, the precise mechanism of MMP‐9 activation by antidepressants has yet to be identified, in particular the intracellular signaling pathway between LPAR1/Gαi/o and MMP‐9. Methods and Results Treatment of rat C6 astroglial cells (C6 cells) with amitriptyline increased Src family tyrosine kinase phosphorylation in a time and concentration‐dependent manner. Amitriptyline‐induced GDNF mRNA expression was blocked by Src family tyrosine kinase inhibitors. In addition, inhibiting Src family tyrosine kinase blocked amitriptyline‐induced zymographic MMP‐9 activation in C6 cells. The amitriptyline‐induced zymographic MMP‐9 activity was completely blocked by selective inhibition of Gαi/o protein and LPAR1. Furthermore, the amitriptyline‐induced Src family tyrosine kinase phosphorylation was blocked by LPAR1, but not MMP‐9 inhibition, indicating that Src family tyrosine kinase involvement is downstream of LPAR1. Conclusions The current findings suggest that the pharmacological effect of antidepressant such as amitriptyline is mediated through an intracellular signaling pathway via the LPAR1/Gαi/o/Src family tyrosine kinase, which leads to MMP‐9 activation and GDNF production.

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Tricyclic Antidepressant Amitriptyline-induced Glial Cell Line-derived Neurotrophic Factor Production Involves Pertussis Toxin-sensitive Gαi/o Activation in Astroglial Cells

Cited by 37 publications

References 62 publications

Targeting the glial-derived neurotrophic factor and related molecules for controlling normal and pathologic pain

Targeting the glial-derived neurotrophic factor and related molecules for controlling normal and pathologic pain

Pharmacological Activation Gi/o Protein Increases Glial Cell Line-Derived Neurotrophic Factor Production through Fibroblast Growth Factor Receptor and Extracellular Signal-Regulated Kinase Pathway in Primary Cultured Rat Cortical Astrocytes

Antidepressant amitriptyline‐induced matrix metalloproteinase‐9 activation is mediated by Src family tyrosine kinase, which leads to glial cell line‐derived neurotrophic factor mRNA expression in rat astroglial cells

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