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

  • Author / Creator
    Dhami, Kamaldeep S
  • 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.

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  • Degree
    Doctor of Philosophy
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    This thesis is made available by the University of Alberta Libraries with permission of the copyright owner solely for non-commercial purposes. This thesis, or any portion thereof, may not otherwise be copied or reproduced without the written consent of the copyright owner, except to the extent permitted by Canadian copyright law.
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  • Institution
    University of Alberta
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  • Department
  • Supervisor / co-supervisor and their department(s)
  • Examining committee members and their departments
    • Dursun, Serdar (Psychiatry)
    • Todd, Kathryn (Centre for Neuroscience)
    • Sipione, Simonetta (Centre for Neuroscience, Pharmacology)
    • Baker, Glen (Psychiatry)
    • Galea, Liisa (Psychology, University of British Colombia)