The Atypical Antidepressant Tianeptine Confers Neuroprotection against Oxygen-Glucose Deprivation

Proregenerative and neuroprotective effects of antidepressants are an important topic of inquiry in neuropsychiatric research. Oxygen-glucose deprivation (OGD) mimics key aspects of ischemic injuryin 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) statistically 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 OGDdemonstrated that OGD induces many pathways relating to cell survival, the inflammation-immune response, synaptic dysregulation and apoptosis, andthatTIA pretreatment counteracted theseeffects 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. Primary neuronal cultures obtained from the cortex of embryonic mice at embryonic day 15 were pretreated with 10 μM TIA at 8 DIV and they were exposed to in vitro ischemic damage via 3 h-OGD at 9 DIV. Total RNA from each condition (CONTROL-VEH, CONTROL-TIA, OGD-VEH and OGD-TIA) was extracted 6 hours after OGD. 4 replicates for each condition was used for RNA-seq.