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Differential and paradoxical roles of new-generation antidepressants in primary astrocytic inflammation
Jian-Hong Zhu
Wenzhou Medical University
Corresponding Author
ORCiD: https://orcid.org/0000-0001-9412-8264
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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.
Keywords
astrocytes, SSRI, SNRI, antidepressant, neuroinflammation
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This is a list of supplementary files associated with this preprint. Click to download.
- SupplementalFigure1.docx
Additional file 1: Supplementary Figure 1. Full blots for the Figures 1 (A), 3 (B) and 4 (C).
- SupplementalFigure2.docx
Additional file 2: Supplementary Figure 2. Inhibition of JNK and STAT3 signaling on A1 and A2 phenotype polarization of astrocytes.
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This preprint is under consideration at Journal of Neuroinflammation. A preprint is a preliminary version of a manuscript that has not completed peer review at a journal. Research Square does not conduct peer review prior to posting preprints. The posting of a preprint on this server should not be interpreted as an endorsement of its validity or suitability for dissemination as established information or for guiding clinical practice.
Learn more about In Review
Research
Differential and paradoxical roles of new-generation antidepressants in primary astrocytic inflammation
Jian-Hong Zhu
Wenzhou Medical University
Corresponding Author
ORCiD: https://orcid.org/0000-0001-9412-8264
Badges
Prescreen
This manuscript passed our Prescreen assessment
Complete author information
Appropriate declaration statements
Potential risks to human health
Prescreen
Peer Review Timeline
CURRENT STATUS: Under Revision
Version 1
Posted 21 Sep, 2020
No community comments so far
Editorial decision: Major Revision
On 03 Nov, 2020
Review #2 received
Received 20 Oct, 2020
Review #1 received
Received 16 Oct, 2020
Reviewer #2 agreed
On 12 Oct, 2020
Reviewer #1 agreed
On 05 Oct, 2020
Reviewers invited
Invitations sent on 04 Oct, 2020
Editor invited
On 18 Sep, 2020
First submitted
On 17 Sep, 2020
Editor assigned
On 17 Sep, 2020
Submission checks complete
On 16 Sep, 2020
Metrics
Comments: 0
PDF Downloads: ...
HTML Views: ...
License:
This work is licensed under a CC BY 4.0 License. Read Full License
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.
Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6
Figure 7
Figure 8