Department of Neurology, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany.
Center for Stroke Research Berlin, Department of Experimental Neurology, Charité-Universitätsmedizin Berlin, Corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany.
Eur Arch Psychiatry Clin Neurosci. 2024 Jun;274(4):777-791. doi: 10.1007/s00406-023-01685-9. Epub 2023 Sep 1.
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.
抗抑郁药的促再生和神经保护作用是神经精神研究中的一个重要课题。氧葡萄糖剥夺（OGD）模拟了体外缺血性损伤的关键方面。在这里，我们研究了 5-羟色胺（5-HT）、西酞普兰（CIT）、氟西汀（FLU）和噻奈普汀（TIA）24 小时预处理对短暂 OGD 后原代小鼠皮质神经元的影响。5-HT（50 μM）通过 MTT 测定显著增强神经元活力，并减少细胞死亡和 LDH 释放。CIT（10 μM）和 FLU（1 μM）并未增强 5-HT 的作用，并且在无血清细胞培养基中没有补充 5-HT 的情况下，两种抗抑郁药均不能提供神经保护作用。相比之下，TIA（10 μM）预处理可导致强烈的神经保护作用，即使在没有 5-HT 的情况下也是如此。此外，TIA 抑制与细胞死亡和缺氧相关的候选基因的 mRNA 转录，并减弱脂质过氧化，这是神经元损伤的标志。最后，对 OGD 后原代神经元进行的深度 RNA 测序表明，OGD 诱导了许多与细胞存活、炎症免疫反应、突触失调和细胞凋亡相关的途径，而 TIA 预处理可抵抗 OGD 的这些作用。总之，这项研究强调了 TIA 无 5-HT 依赖性神经保护作用的相对优势，并确定了涉及的分子途径。
