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The effects of antidepressants on the phenotype of activated microglia and ischemia-injured cortical neurons Open Access

Descriptions

Other title
Subject/Keyword
Inflammation
Microglia
Excitotoxicity
Ischemia
Antidepressants
Type of item
Thesis
Degree grantor
University of Alberta
Author or creator
Dhami, Kamaldeep S
Supervisor and department
Todd, Kathryn (Centre for Neuroscience)
Examining committee member and department
Todd, Kathryn (Centre for Neuroscience)
Galea, Liisa (Psychology, University of British Colombia)
Dursun, Serdar (Psychiatry)
Sipione, Simonetta (Centre for Neuroscience, Pharmacology)
Baker, Glen (Psychiatry)
Department
Centre for Neuroscience
Specialization

Date accepted
2013-07-03T14:43:15Z
Graduation date
2013-11
Degree
Doctor of Philosophy
Degree level
Doctoral
Abstract
Depression is one of the most common disorders appearing following a stroke and is also a major factor limiting recovery and rehabilitation in stroke patients. Several antidepressants have shown to have anti-inflammatory properties within the central nervous system (CNS). The major source of pro-inflammatory factors within the CNS is from activated microglia, the innate immune cells of the CNS. Antidepressants have been shown to promote midbrain and hippocampal neuronal survival following an ischemic insult and these effects are mediated through the anti-inflammatory effects on microglia, but the effects on cortical neuronal survival after this insult have yet to be investigated. The present study aimed to test and compare antidepressants from three distinct classes (tricylics, monoamine oxidase inhibitors, and selective serotonin reuptake inhibitors [SSRIs]) on the release of inflammatory factors and amino acids from activated microglia and to determine whether altering this release could affect cortical neuronal viability after an ischemic insult. Primary microglia were treated with 1 μg/ml LPS and/or 10 μM antidepressants, and the various factors released into the medium were assayed. Co-cultures consisting of microglia and primary cortical neurons were used to assess the effects of antidepressant-treated activated microglia on the viability of ischemia-injured neurons. Of the antidepressants tested, most decreased the release of the pro-inflammatory factors nitric oxide, tumor necrosis factor-alpha, and interleukin 1- beta from activated microglia. Fluoxetine and citalopram, the SSRIs, also decreased the release of the amino acids glutamate and D-serine from LPS-activated microglia. Injured cortical neurons co-cultured with LPS-activated microglia pre-treated with fluoxetine and citalopram showed greater survival compared to injured neurons co-cultured with untreated activated microglia. Studies using NMDA receptor antagonists demonstrated that the release of glutamate and D-serine from microglia was a principal factor mediating cortical neuronal survival. In addition, we found that one possible mechanism behind the attenuation of microglial glutamate and D-serine release following fluoxetine treatment is through the induction of microglial apoptosis. Our results demonstrated for the first time that fluoxetine and citalopram decrease the release of glutamate and D- serine from LPS-activated microglia and this increases the survival of injured cortical neurons after co-culture. Fluoxetine was also shown to induce the apoptotic death of microglia.
Language
English
DOI
doi:10.7939/R3T14TX9J
Rights
Permission is hereby granted to the University of Alberta Libraries to reproduce single copies of this thesis and to lend or sell such copies for private, scholarly or scientific research purposes only. Where the thesis is converted to, or otherwise made available in digital form, the University of Alberta will advise potential users of the thesis of these terms. The author reserves all other publication and other rights in association with the copyright in the thesis and, except as herein before provided, neither the thesis nor any substantial portion thereof may be printed or otherwise reproduced in any material form whatsoever without the author's prior written permission.
Citation for previous publication
Dhami, K.S., Baker, G.B., Todd, K. G. 2013. Fluoxetine and citalopram decrease microglial release of glutamate and D-serine to promote cortical neuronal viability following ischemic insult. Submitted to Molecular and Cellular Neuroscience. Manuscript accepted pending revisions.

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File size: 28178226
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File author: Kamaldeep Dhami
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