Interaction of Paroxetine with Mitochondrial Proteins Mediates Neuroprotection

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 HIVinfected individuals.

Conditional Human Immunodeficiency Virus Transactivator of Transcription Protein Expression Induces Depression-like Effects and Oxidative Stress

“…Among its signaling properties, Tat protein increases Tumor necrosis factor alpha expression (13,49,74,76) which in the short-term can increase expression of the antioxidant response element transcription factor Nuclear factor-erythroid 2-related factor 2 (Nrf2), resulting in increased GSH production (102). Tat protein also increases Nrf2 expression and activity through the activation of glutamatergic N-methyl-D-aspartate (NMDA) receptors and the enzyme spermine oxidase (103).…”

“…We also characterized Tat’s effects on MFC temperature, which can be determined in proton spectra (73). Because Tat increases Tumor Necrosis Factor alpha levels (13,74–76), which increase expression of mitochondrial uncoupling proteins (77–81) that dissipate oxidative stress in the form of heat (82), we hypothesized that Tat protein expression in GT-tg mice would increase MFC temperature.…”

Striatal Magnetic Resonance Spectroscopy Abnormalities in Young Adult Sapap3 Knockout Mice

“…Thus, striatal hypermetabolism and anxiety in SAPAP3 KO mice could both enhance oxidative stress and reduce PV+ interneuron densities. Although fluoxetine’s rapid normalization of compulsive behavior and anxiety in SAPAP3 KO mice (6) may be related to serotonin uptake inhibition, its efficacy could be mediated in part by fluoxetine’s ability to buffer mitochondrial oxidative stress (55). Other serotonin uptake inhibitors and tricyclic antidepressants with efficacy for treating OCRD exhibit antioxidant properties (55), and their antioxidant effects could in part mediate clinical response.…”

Transgenic mice expressing HIV-1 envelope protein gp120 in the brain as an animal model in neuroAIDS research

“…Less neural progenitor proliferation in the presence of viral gp120 resulted in a smaller pool of progenitor cells to differentiate into neurons, thus impairing neurogenesis (Okamoto et al , 2007). Inhibition of hippocampal neurogenesis in GFAP-gp120tg mice was confirmed in subsequent studies, which implied roles for serotonin, cyclin-dependent kinase 5 (CDK5), fibroblast growth factor (FGF), nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), cannabinoid (CB) 2 receptor, fatty acid amide hydrolase (FAAH), Cox2 and prostaglandin E 2 (PGE 2 ) (Avraham et al , 2015; Avraham et al , 2014b; Fields et al , 2014; Lee et al , 2013; Steiner et al , 2015). One study found in brain specimen of HIVE patients and HIVgp120tg mouse brains evidence of aberrant activity of CDK5 and hyperphosphorylation of collapsin-response mediator protein-2 (CRMP2) which in turn can impair neurite outgrowth (Crews et al , 2011).…”

“…The successful approaches included CDK5 knockout, the cell cycle inhibitor roscovitine, the tyrosine kinase inhibitor sunitinib and an exercise-induced increase of BDNF expression (Fields et al , 2014; Lee et al , 2013; Patrick et al , 2011; Wrasidlo et al , 2014). However, exercise and selective serotonin re-uptake inhibitors (SSRI) also restored hippocampal neurogenesis in GFAP-gp120tg mice (Lee et al , 2011; Steiner et al , 2015). The exact mechanism(s) remain to be elucidated but appear to involve reduced susceptibility to excitotoxic injury.…”