Several Antidepressant Classes Increase Early Growth Response in Astrocytes

A study of antidepressants reveals how treatment helps depression management.

Researchers in Japan have shown that several different classes of antidepressants increase early growth responses in astrocytes, star-shaped glial cells, which could help develop new treatments.

Amitriptyline is a prototypical antidepressant that is currently used worldwide. Generally, effects of antidepressants such as amitriptyline in depressive patients become evident after treatment for a few weeks. However, no study has investigated the reasons why effects are not immediately evident.

Previous studies have shown that amitriptyline increases the mRNA expression of fibroblast growth factor 2 (FGF2) in rat astrocytes, not neurons, slowly over 24 hours. However, the cellular mechanism that leads to the expression of FGF2 following amitriptyline treatment remains unclear.

In this study, the research group treated rat primary cultured astrocytes with amitriptyline. They found that it results in the activation of receptor tyrosine kinases (RTK; fibroblast growth factor receptor [FGFR] and epidermal growth factor receptor [EGFR]), which in turn increased FGF2 mRNA expression.

Professor Yoshihiro Nakata at Hiroshima University and Dr Minoru Takebayashi at National Hospital Organization Kure Medical Center and Chugoku Cancer Center said, “activated RTK induces the phosphorylation of extracellular signal-regulated kinase 1/2 and increases EGR1 mRNA and protein expression followed by FGF2 mRNA expression.”

Diagram of the treatment of primary cultured astrocytes with amitriptyline activates matrix metalloproteinases.
This image shows the treatment of primary cultured astrocytes with amitriptyline activates matrix metalloproteinases (MMPs) and receptor tyrosine kinases (RTKs, i.e., fibroblast growth factor receptor [FGFR] and epidermal growth factor receptor [EGFR]). Activated RTKs increase the mRNA and protein expression of EGR1, which in turn increases FGF2 mRNA expression.Credit: The researchers/Hiroshima University.

Professor Nakata said, “the current findings expand previous findings, in that the transcription factor EGR1 could be the de novo synthesized protein that is necessary for increasing FGF2 mRNA expression evoked by amitriptyline treatment.”

The amitriptyline-induced signaling cascade is essential for the expression of FGF2 mRNA in primary cultured astrocytes. This cascade could be used to guide the development of antidepressants with novel mechanisms.

[divider]About this neuropharmacology research[/divider]

Funding: The study was supported by the Japan Society for the Promotion of Science KAKENHI, Takeda Science Foundation, Naito Foundation, and SENSHIN Medical Research Foundation.

Source: Norifumi Miyokawa – Hiroshima University
Image Source: The image is credited to The researchers/Hiroshima University
Original Research: Abstract for “Fibroblast growth factor 2 mRNA expression evoked by amitriptyline involves extracellular signal-regulated kinase-dependent early growth response 1 production in rat primary cultured astrocytes” by Naoto Kajitani, Kazue Hisaoka-Nakashima, Mami Okada-Tsuchioka, Mayu Hosoi, Toshiki Yokoe, Norimitsu Morioka, Yoshihiro Nakata and Minoru Takebayashi in Journal of Neurochemistry. Published online August 6 2015 doi:10.1111/jnc.13247


Abstract

Fibroblast growth factor 2 mRNA expression evoked by amitriptyline involves extracellular signal-regulated kinase-dependent early growth response 1 production in rat primary cultured astrocytes

Recently, we demonstrated that several antidepressants including amitriptyline increased fibroblast growth factor 2 (FGF2) mRNA expression slowly over 24 h through de novo protein synthesis in rat primary cultured astrocytes. This study defined the signaling cascade that mediates amitriptyline-induced FGF2 production in rat primary cultured astrocytes. Amitriptyline treatment significantly increased early growth response 1 (EGR1), a transcription factor known to regulate FGF2 expression. Knockdown of EGR1 using siRNA blocked amitriptyline-evoked FGF2 mRNA expression. Treatment with several different classes of antidepressants leads to expression of EGR1 mRNA as well as FGF2 mRNA. These results confirm that EGR1 production is likely to be indispensable for the amitriptyline-evoked FGF2 mRNA expression. Signal transduction inhibitors were used to elaborate the cellular signaling cascade that leads to EGR1-mediated FGF2 expression following amitriptyline treatment. Amitriptyline-evoked EGR1-mediated FGF2 mRNA expression was blocked by mitogen-activated protein kinase/extracellular signal-regulated kinase kinase (MEK)1/2 inhibitor. Furthermore, extracellular signal-regulated kinase/EGR1-mediated FGF2 mRNA expression evoked by amitriptyline was blocked by inhibitors of the FGF receptor, epidermal growth factor receptor (EGFR), and matrix metalloproteinase. Taken together, these results demonstrate that amitriptyline increases FGF2 mRNA expression through a matrix metalloproteinase/receptor tyrosine kinases (RTK) (FGF receptor and EGFR)/extracellular signal-regulated kinase/EGR1 signaling pathway in rat primary cultured astrocytes.

Recent studies suggest that fibroblast growth factor 2 (FGF2) is involved in the antidepressant effect in the model of depression. The production of ERK-dependent early growth response 1 (EGR1) is a crucial part of the amitriptyline-induced FGF2 expression signaling cascade in rat primary cultured astrocytes. The findings elaborate an astrocytic mechanism that could be used to develop antidepressants.

“Fibroblast growth factor 2 mRNA expression evoked by amitriptyline involves extracellular signal-regulated kinase-dependent early growth response 1 production in rat primary cultured astrocytes” by Naoto Kajitani, Kazue Hisaoka-Nakashima, Mami Okada-Tsuchioka, Mayu Hosoi, Toshiki Yokoe, Norimitsu Morioka, Yoshihiro Nakata and Minoru Takebayashi in Journal of Neurochemistry. Published online August 6 2015 doi:10.1111/jnc.13247

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