The atypical antidepressant tianeptine confers neuroprotection against oxygen–glucose deprivation

Abstract

Proregenerative and neuroprotective effects of antidepressants are an important topic of inquiry in neuropsychiatric research. Oxygen–glucose deprivation (OGD) mimics key aspects of ischemic injury in vitro. Here, we studied the effects of 24-h pretreatment with serotonin (5-HT), citalopram (CIT), fluoxetine (FLU), and tianeptine (TIA) on primary mouse cortical neurons subjected to transient OGD. 5-HT (50 μM) significantly enhanced neuron viability as measured by MTT assay and reduced cell death and LDH release. CIT (10 μM) and FLU (1 μM) did not increase the effects of 5-HT and neither antidepressant conferred neuroprotection in the absence of supplemental 5-HT in serum-free cell culture medium. By contrast, pre-treatment with TIA (10 μM) resulted in robust neuroprotection, even in the absence of 5-HT. Furthermore, TIA inhibited mRNA transcription of candidate genes related to cell death and hypoxia and attenuated lipid peroxidation, a hallmark of neuronal injury. Finally, deep RNA sequencing of primary neurons subjected to OGD demonstrated that OGD induces many pathways relating to cell survival, the inflammation-immune response, synaptic dysregulation and apoptosis, and that TIA pretreatment counteracted these effects of OGD. In conclusion, this study highlights the comparative strength of the 5-HT independent neuroprotective effects of TIA and identifies the molecular pathways involved.

Resolving a paradox: antidepressants, neuroinflammation, and neurodegeneration

“…A naturally arising question in this context is whether existing antidepressants can meaningfully reduce neuroinflammation [38]. Though this possibility has not been systematically evaluated in patients with MDD, several studies have examined the "anti-neuroinflammatory" potential of antidepressant drugs in cell lines or animal models relevant to dementia [62][63][64][65][66][67][68][69][70][71][72][73][74][75][76][77][78][79]. Studies examining the beneficial effects of these drugs on neuroinflammation in pre-clinical models are described in Table 1.…”

“…Tranylcypromine Reduces LPS-induced expression of IL-1β IL-6, reduces p-STAT3 and NF-κB nuclear translocation, and reduces TLR4/ERK signaling in mouse microglia; downregulates Aβ-induced microglial activation in a mouse model of AD [75] Tianeptine Reduces gp120-induced apoptosis and stimulation of caspase-3, suppresses NOS, and inhibits NF-κB transcription in human astroglial cells [76] Inhibits expression of plasminogen activator inhibitor-1 (Serpine-1) and reduces lipid peroxidation and apoptosis in mouse cortical neurons exposed to oxygenglucose deprivation [77] Trazodone Reduces microglial NLRP3 inflammasome expression, phosphorylated p38 MAPK and ATF4 levels, and tau levels in a mouse model of tauopathy; improves sleep and memory [81] Vortioxetine Restores levels of TGF-β and inhibits Aβ-induced oxidative stress in a mouse model of AD; protects against behavioral changes and memory deficits [69] Reduces caspase-3 expression and α-synuclein deposition in a rotenone-induced rat model of PD; improves motor, cognitive, and behavioral functioning [78] Others Agomelatine Reduces expression of aging-related proteins, caspase-3, and glutamate-included excitotoxicity; stabilizes endoplasmic reticulum and mitochondrial membranes in a rat model of aging [79] Aβ: amyloid-beta protein; ATF4: activating transcription factor 4; CXCL1: chemokine ligand 1; ERK: extracellular signalregulated kinase; gp120: glycoprotein 120; HD: Huntington's disease; IFN-γ: interferon-gamma; MAPK: mitogen-activated protein kinase; LPS: lipopolysaccharide; MSA: multiple systems atrophy; NF-κB: nuclear factor kappa B; NLRP3: Nod-like receptor protein 3; NO: nitric oxide; NOS: NO synthase; PD: Parkinson's disease; p-STAT3: phosphorylated signal transducer and activator of transcription protein 3; TGF-β: transforming growth factor-beta; TLR4: toll-like receptor 4…”