Table 1.
Summary of antidepressant actions with neuroprotective effects.
| Mechanism | Neuroprotective effect of individual compounds or drug classes |
|---|---|
| Inflammation | ▪ Antidepressants reduce peripheral pro-inflammatory markers and increase anti-inflammatory cytokinesa |
| ▪ SSRIs limit microglial and astroglial inflammatory activation (e.g. TNF-α-, NO production) | |
| ▪ Fluoxetine promotes downregulation of genes involved in pro-inflammatory pathways (e.g. IL-6, NF-κb, TNF and acute-phase response signaling)b | |
| ▪ Bupropion lowers production of TNF-α and IFN-γb | |
| ▪ Venlafaxine augments TGF-β release, reduces secretion of IL-6, IFN-γ and changes microglial phenotype from activated to resting morphologyb | |
| ▪ Moclobemide exerts anti-inflammatory effects by affecting the balance between pro- and anti-inflammatory cytokines (IL-1β, TNF-α/IL-10)b | |
| Neurotransmitter metabolism | ▪ Antidepressants influence monoamine metabolism and increase levels of 5-HT and NAa |
| ▪ NA has anti-inflammatory, neurotrophic and neuroprotective effects | |
| ▪ NA influences microglial migration, Aβ phagocytosis and effects amyloid deposition | |
| ▪ 5-HT increases release of non-amyloidogenic APP via 5-HT2A and 5-HT2C receptors thereby disfavoring the formation of neurotoxic Aβ | |
| HPA axis and neurogenesis | ▪ Antidepressants increase neurogenesis, reverse reduction in dendrite number/length and GABAergic cell lossb |
| ▪ increase the proliferation of neural progenitors in the subgranulate zone of the hippocampus and gliogenesis (i.e. oligodendrocytes) in the prefrontal cortex | |
| ▪ increase BDNF transcription by BDNF-TrkB signaling, MAPK and PI3K pathways | |
| ▪ effect Wnt-GSK-3 and influence growth and guidance of neurons and dendritic arborization | |
| ▪ Fluoxetine and Moclobemide reverse stress-induced changes in hippocampal neurogenesis, inhibit apoptosis in hippocampal primary neurons and increase BDNF expressionb | |
| ▪ Fluoxetin increases the sizes of hippocampal CA1 and dentate gyrus, remodels synaptic plasticity of neurons in the hippocampus (activation of CREB protein/BDNF signaling pathway)b | |
| Amyloid-β | ▪ Antidepressants reduce amyloid plaque burden by shifting the balance from pro- toward non-amyloidogenic APP processinga |
| ▪ Antidepressants up-regulate cAMP cascade in hippocampus and cerebral cortex leading to enhancement of synaptic plasticityb | |
| ▪ SSRIs reduce ISF Aβ levels in animal models and CSF Aβ concentrations in humans | |
| ▪ Citalopram suppresses generation of Aβ and decreases levels of insoluble Aβ 40 in hippocampal and cortical tissue | |
| ▪ Fluoxetine prevents the increase of Aβ accumulation | |
| ▪ Tranylcypromine prevents Aβ-induced neuronal death and Aβ aggregationb | |
| ▪ Amitriptyline inhibits Aβ1–42-induced activation of ERK1/2 and exerts neuroprotective effects against Aβ1–42-induced neurotoxicityb | |
| Tau | ▪ Escitalopram ameliorates forskolin- and Aβ1–42-induced tau hyperphosphorylation in primary hippocampal neurons through activation of PKA and 5-HT1A receptor mediated Akt/GSK-3β pathwayb |
SSRIs selective serotonin reuptake inhibitors, TNF-α tumor necrosis factor alpha, NO nitric oxide, IL-6 Interleukin 6, NF-κb nuclear factor kappa-light-chain-enhancer of activated B cells, IFN-γ interferon gamma, TGF-β transforming growth factor-β, IL-1β Interleukin 1 beta, IL-10 Interleukin 10, 5-HT 5-hydroxytryptamine, NA noradrenalin, APP amyloid precursor protein, HPA axis hypothalamic-pituitary-adrenal axis, BDNF brain-derived neurotrophic factor, CREB cAMP-response element-binding protein, BDNF-TrkB brain-derived neurotrophic factor tropomyosin related kinase B, MAPK mitogen-activated protein kinase, PI3K phosphatidyl inositol 3-kinase-Akt pathways, Wnt-GSK-3 Wnt-glycogen synthase kinase-3, ERK1/2 extracellular signal-regulated kinase 1 and 2, PKA protein kinase A.
aIn animal and human studies.
bIn animal studies.