Neuroscience Postgraduate Program, Center of Biological Sciences, Universidade Federal de Santa Catarina, Florianópolis, 88040-900, SC, Brazil; Department of Biochemistry, Center of Biological Sciences, Universidade Federal de Santa Catarina, Florianópolis, 88040-900, SC, Brazil.
Laboratory of Evaluation of Bioactive Substances, Department of Natural Sciences, Universidade Regional de Blumenau, CEP 89030-903, Blumenau, SC, Brazil.
Neurochem Int. 2020 Oct;139:104797. doi: 10.1016/j.neuint.2020.104797. Epub 2020 Jul 9.
Augmentative treatment is considered the best second-option when a first-choice drug has partial limitations, particularly by allowing antidepressant dose reduction. Considering that ketamine has significant knock-on effects, this study investigated the effects of a single coadministration with subthreshold doses of ketamine plus guanosine in a corticosterone (CORT)-induced animal model of depression and the role of anti-inflammatory and antioxidant pathways. CORT administration (20 mg/kg, p.o. for 21 days) increased the immobility time in the tail suspension test (TST) and the grooming latency in the splash test (SPT), as well as reduced the total time of grooming in the SPT. These behavioral alterations were accompanied by impaired hippocampal slices viability, elevated immunocontent of nuclear factor-kappa B (NF-κB) and indoleamine-2,3-dioxygenase 1 (IDO-1), and reduced immunocontent of glucocorticoids receptor (GR), glutamate transporter (GLT-1), nuclear factor-erythroid 2-related factor 2 (Nrf2), and heme oxygenase-1 (HO-1) in the hippocampus. CORT also decreased the thioredoxin reductase activity in the hippocampus, while reduced the glutathione reductase activity and non-protein thiols levels in both hippocampus and prefrontal cortex. In addition, elevated content of malondialdehyde and protein carbonyl was also observed in the hippocampus and prefrontal cortex of CORT-treated mice. Of note, a single administration of ketamine (0.1 mg/kg, i.p.) plus guanosine (0.01 mg/kg, p.o.) attenuated the depressive-like behavior and hippocampal slices impairments induced by CORT. The behavioral response obtained by the combined administration of these drugs was paralleled by the reestablishment of the CORT-induced molecular alterations on hippocampal GR, NF-κB, IDO-1, and GLT-1 immunocontent. Moreover, CORT-induced alterations on the antioxidant enzyme activity and oxidative stress markers were partially restored by ketamine plus guanosine treatment. Taken together, these findings suggest that guanosine might potentiate the effects of ketamine on inflammatory and oxidative markers that are elevated in depression.
增效治疗被认为是首选药物存在部分局限性时的最佳第二选择，特别是可以降低抗抑郁药的剂量。考虑到氯胺酮具有显著的连锁反应，本研究调查了氯胺酮与低剂量鸟苷联合给药在皮质酮（CORT）诱导的抑郁动物模型中的作用，以及抗炎和抗氧化途径的作用。CORT 给药（20mg/kg，口服，共 21 天）增加了悬尾试验（TST）中的不动时间和飞溅试验（SPT）中的梳理潜伏期，并减少了 SPT 中的总梳理时间。这些行为改变伴随着海马切片活力受损、核因子-κB（NF-κB）和吲哚胺 2,3-双加氧酶 1（IDO-1）的免疫含量升高，以及糖皮质激素受体（GR）、谷氨酸转运体（GLT-1）、核因子-红细胞 2 相关因子 2（Nrf2）和血红素加氧酶-1（HO-1）的免疫含量降低。CORT 还降低了海马中的硫氧还蛋白还原酶活性，同时降低了海马和前额叶皮层中的谷胱甘肽还原酶活性和非蛋白巯基水平。此外，还观察到 CORT 处理的小鼠海马和前额叶皮层中的丙二醛和蛋白质羰基含量升高。值得注意的是，单次给予氯胺酮（0.1mg/kg，腹腔注射）加鸟苷（0.01mg/kg，口服）可减轻 CORT 诱导的抑郁样行为和海马切片损伤。联合给予这些药物的行为反应与海马 GR、NF-κB、IDO-1 和 GLT-1 免疫含量的 CORT 诱导分子改变的重建平行。此外，氯胺酮加鸟苷治疗部分恢复了 CORT 诱导的抗氧化酶活性和氧化应激标志物的改变。综上所述，这些发现表明，鸟苷可能增强氯胺酮对炎症和氧化标志物的作用，这些标志物在抑郁症中升高。
