Interaction of Paroxetine with Mitochondrial Proteins Mediates Neuroprotection

Joseph P. Steiner, Muznabanu Bachani, Brett Wolfson-Stofko, Myoung Hwa Lee, Tonguang Wang, Guanhan Li, Wenxue Li, David Strayer, Norman J. Haughey, Avindra Nath

Research output: Contribution to journalArticlepeer-review

Abstract

There are severe neurological complications that arise from HIV infection, ranging from peripheral sensory neuropathy to cognitive decline and dementia for which no specific treatments are available. The HIV proteins secreted from infected macrophages, gp120 and Tat, are neurotoxic. The goal of this study was to screen, identify and develop neuroprotective compounds relevant to HIV-associated neurocognitive disorders (HAND). We screened more than 2000 compounds that included FDA approved drugs for protective efficacy against oxidative stress-mediated neurodegeneration and identified selective serotonin reuptake inhibitors (SSRIs) as potential neuroprotectants. Numerous SSRIs were then extensively evaluated as protectants against neurotoxicity as measured by changes in neuronal cell death, mitochondrial potential, and axodendritic degeneration elicited by HIV Tat and gp120 and other mitochondrial toxins. While many SSRIs demonstrated neuroprotective actions, paroxetine was potently neuroprotective (100 nM potency) against these toxins in vitro and in vivo following systemic administration in a gp120 neurotoxicity model. Interestingly, the inhibition of serotonin reuptake by paroxetine was not required for neuroprotection, since depletion of the serotonin transporter had no effect on its neuroprotective properties. We determined that paroxetine interacts selectively and preferentially with brain mitochondrial proteins and blocks calcium-dependent swelling but had less effect on liver mitochondria. Additionally, paroxetine induced proliferation of neural progenitor cells in vitro and in vivo in gp120 transgenic animals. Therefore, SSRIs such as paroxetine may provide a novel adjunctive neuroprotective and neuroregenerative therapy to treat HIV-infected individuals.

Original languageEnglish (US)
Pages (from-to)200-216
Number of pages17
JournalNeurotherapeutics
Volume12
Issue number1
DOIs
StatePublished - Jan 1 2015

Keywords

  • HAND
  • Mitochondria
  • Neuroprotective
  • Paroxetine
  • SSRI

ASJC Scopus subject areas

  • Pharmacology
  • Clinical Neurology
  • Pharmacology (medical)

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