Antidepressants increase neural progenitor cells in the human hippocampus

Boldrini, Maura; Underwood, Mark D.; Hen, René; Rosoklija, Gorazd; Dwork, Andrew J.; Mann, J. John; Arango, Victoria

doi:10.1038/npp.2009.75

Cited by 587 publications

(497 citation statements)

References 80 publications

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“…These studies confirm our previous observations of paroxetine on NPC [12]. Several studies have shown that antidepressants increase hippocampal neurogenesis in both animals and humans [39,40] and hippocampal neurogenesis has been suggested to be a key factor in the action of antidepressant drugs [41,42]. Suppression of hippocampal neurogenesis by irradiation prevents the effects of fluoxetine and imipramine [41].…”

Section: Discussionsupporting

confidence: 90%

Interaction of Paroxetine with Mitochondrial Proteins Mediates Neuroprotection

et al. 2015

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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.

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Section: Discussionsupporting

confidence: 90%

Interaction of Paroxetine with Mitochondrial Proteins Mediates Neuroprotection

et al. 2015

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“…Determinants of hippocampal volume in MDD are not known. Like others (Reif et al, 2006), we did not detect fewer mitotic cells (Boldrini et al, 2009) or neural progenitor cells (NPCs) in the DG postmortem (Boldrini et al, 2009(Boldrini et al, , 2012 in untreated MDD subjects (o58-60 y old) compared to those with no major psychopathology. Notably, blocking (Santarelli et al, 2003) or blunting (Vollmayr et al, 2003) hippocampal proliferation in adulthood is not sufficient to induce depression-like behavior in mice.…”

Section: Introductionmentioning

confidence: 83%

Hippocampal Granule Neuron Number and Dentate Gyrus Volume in Antidepressant-Treated and Untreated Major Depression

Boldrini

Santiago

Hen

et al. 2013

Neuropsychopharmacol

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282

210

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Smaller hippocampal volume is reported in major depressive disorder (MDD). We hypothesize that it may be related to fewer granule neurons (GN) in the dentate gyrus (DG), a defect possibly reversible with antidepressants. We studied age-, sex-, and postmortem interval-matched groups: no major psychopathology (controls); unmedicated-MDD; and MDD treated with serotonin reuptake inhibitors (MDD*SSRI) or tricyclics (MDD*TCA). Frozen right hippocampi were fixed, sectioned (50 mm), immunostained with neuronal nuclear marker (NeuN), and counterstained with hematoxylin. GN and glial number, and DG and granule cell layer (GCL) volumes were stereologically estimated. Fewer GNs in the anterior DG were present in unmedicated-MDDs compared with controls (p ¼ 0.013). Younger age of MDD onset correlated with fewer GNs (p ¼ 0.021). Unmedicated-MDDs had fewer mid-DG GNs than MDD*SSRIs (p ¼ 0.028) and controls (p ¼ 0.032). Anterior GCL glial number did not differ between groups. Anterior/mid GCL volume was smaller in unmedicated-MDDs vs controls (p ¼ 0.008) and larger in MDD*SSRIs vs unmedicated-MDDs (po0.001), MDD*TCAs (po0.001), and controls (po0.001). Anterior GCL volume and GN number (r ¼ 0.594, p ¼ 0.001), and mid DG volume and GN number (r ¼ 0.398, p ¼ 0.044) were correlated. Anterior DG capillary density correlated with GN number (p ¼ 0.027), and with GCL (p ¼ 0.024) and DG (r ¼ 0.400, p ¼ 0.047) volumes. Posterior DG volume and GN number did not differ between groups. Fewer GNs in unmedicated-MDD without fewer neuronal progenitor cells, as previously reported, suggests a cell maturation or survival defect, perhaps related to MDD duration. This may contribute to a smaller hippocampus and is potentially reversed by SSRIs. Postmortem studies are correlative and animal studies are needed to test implied causal relationships.

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“…The relevance of neurogenesis to depression and antidepressant responses in humans has been examined, although the evidence is limited to a few post-mortem studies. A recent report shows that the rate of new cell birth is significantly increased in depressed subjects receiving antidepressant treatment prior to and at the time of death [25]. However, cell birth was not decreased in untreated depressed subjects.…”

Section: Regulation Of Neurogenesis By Stress and Antidepressant Treamentioning

confidence: 99%

A neurotrophic hypothesis of depression: role of synaptogenesis in the actions of NMDA receptor antagonists

Duman

2012

Phil. Trans. R. Soc. B

279

188

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Molecular and cellular studies have demonstrated opposing actions of stress and antidepressant treatment on the expression of neurotrophic factors, particularly brain-derived neurotrophic factor, in limbic structures of the brain. These changes in neurotrophic factor expression and function result in structural alterations, including regulation of neurogenesis, dendrite length and spine density in hippocampus and prefrontal cortex (PFC). The deleterious effects of stress could contribute to the reduced volume of these brain regions in depressed patients. Conversely, the actions of antidepressant treatment could be mediated in part by blocking or reversing the atrophy caused by stress and depression. Recent studies have identified a novel, rapid-acting antidepressant, ketamine, in treatment-resistant depressed patients that addresses the limitations of currently available agents (i.e. delayed onset of action and low response rates). We have found that ketamine, an N-methyl-D-aspartate (NMDA) receptor antagonist, causes a rapid induction of synaptogenesis and spine formation in the PFC via stimulation of the mammalian target of the rapamycin signalling pathway and increased synthesis of synaptic proteins. These effects of ketamine rapidly reverse the atrophy of PFC neurons caused by chronic stress and correspond to rapid behavioural actions of ketamine in models of depression. Characterization of a novel signalling pathway also identifies new cellular targets that could result in rapid and efficacious antidepressant actions without the side effects of ketamine.

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Antidepressants increase neural progenitor cells in the human hippocampus

Cited by 587 publications

References 80 publications

Interaction of Paroxetine with Mitochondrial Proteins Mediates Neuroprotection

Interaction of Paroxetine with Mitochondrial Proteins Mediates Neuroprotection

Hippocampal Granule Neuron Number and Dentate Gyrus Volume in Antidepressant-Treated and Untreated Major Depression

A neurotrophic hypothesis of depression: role of synaptogenesis in the actions of NMDA receptor antagonists

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