Neurochemical Research Unit, University of Alberta, Edmonton, Canada; Center for Neuroscience, University of Alberta, Edmonton, Canada.
Mol Cell Neurosci. 2013 Sep;56:365-74. doi: 10.1016/j.mcn.2013.07.006. Epub 2013 Jul 19.
Depression is one of the most common disorders appearing following a stroke, and is also a major factor limiting recovery and rehabilitation in stroke patients. Antidepressants are the most common prescribed treatment for depression and have shown to have anti-inflammatory properties within the central nervous system (CNS). The major source of pro-inflammatory factors within the CNS is from activated microglia, the innate immune cells of the CNS. Antidepressants have been shown to promote midbrain and hippocampal neuronal survival following an ischemic insult and this survival is mediated through the anti-inflammatory effects on microglia, but the effects on cortical neuronal survival after this insult have yet to be investigated. The present study aimed to test and compare antidepressants from three distinct classes (tricyclics, monoamine oxidase inhibitors, and selective serotonin-reuptake inhibitors [SSRIs]) on the release of inflammatory factors and amino acids from activated microglia and whether altering this release could affect cortical neuronal viability after an ischemic insult. Primary microglia were treated with 1 μg/ml LPS and/or 10 μM antidepressants, and the various factors released into medium were assayed. Co-cultures consisting of microglia and primary cortical neurons were used to assess the effects of antidepressant-treated activated microglia on the viability of ischemic injured neurons. Of the antidepressants tested, most decreased the release of the proinflammatory factors nitric oxide, tumor necrosis factor-alpha, and interleukin 1-beta from activated microglia. Fluoxetine and citalopram, the SSRIs, decreased the release of the amino acids glutamate and d-serine from LPS-activated microglia. oxygen-glucose deprived (OGD) cortical neurons cocultured with LPS-activated microglia pre-treated with fluoxetine and citalopram showed greater survival compared to injured neurons co-cultured with untreated activated microglia. Microglial release of glutamate and d-serine was shown to be the most important factor mediating neuronal survival following antagonism studies. To our knowledge, our results demonstrate for the first time that fluoxetine and citalopram decrease the release of glutamate and d-serine from LPS-activated microglia and this causes an increase in the survival of OGD-injured cortical neurons after co-culture.
抑郁症是中风后最常见的疾病之一，也是限制中风患者康复的主要因素。抗抑郁药是治疗抑郁症最常用的药物，已被证明在中枢神经系统（CNS）中具有抗炎特性。CNS 中促炎因子的主要来源是活化的小胶质细胞，CNS 的固有免疫细胞。抗抑郁药已被证明可促进缺血性损伤后脑中和海马神经元的存活，这种存活是通过对小胶质细胞的抗炎作用介导的，但这种作用对皮质神经元存活的影响尚未得到研究。本研究旨在测试和比较来自三个不同类别的抗抑郁药（三环类抗抑郁药、单胺氧化酶抑制剂和选择性 5-羟色胺再摄取抑制剂[SSRIs]）对活化小胶质细胞释放炎症因子和氨基酸的影响，以及改变这种释放是否会影响缺血性损伤后皮质神经元的活力。原代小胶质细胞用 1μg/ml LPS 和/或 10μM 抗抑郁药处理，然后测定释放到培养基中的各种因子。将小胶质细胞和原代皮质神经元共培养，以评估经抗抑郁药处理的活化小胶质细胞对缺血性损伤神经元活力的影响。在所测试的抗抑郁药中，大多数药物可减少 LPS 激活的小胶质细胞释放促炎因子一氧化氮、肿瘤坏死因子-α和白细胞介素 1-β。氟西汀和西酞普兰，SSRIs，减少了 LPS 激活的小胶质细胞释放谷氨酸和 D-丝氨酸。与未经处理的活化小胶质细胞共培养的损伤神经元相比，与用氟西汀和西酞普兰预处理的 LPS 激活的小胶质细胞共培养的氧葡萄糖剥夺（OGD）皮质神经元的存活增加。拮抗研究表明，小胶质细胞释放谷氨酸和 D-丝氨酸是介导神经元存活的最重要因素。据我们所知，我们的研究结果首次表明，氟西汀和西酞普兰可减少 LPS 激活的小胶质细胞释放谷氨酸和 D-丝氨酸，这导致共培养后 OGD 损伤的皮质神经元存活率增加。
