Özler Ceyda, Özkan Esra, Shomalizadeh Narges, Kesibi Judy, Sapancı Selin, Salman Fatmanur Akpunar, Uçar Ege Anıl, Gürsoy-Özdemir Yasemin
Koç University Research Center for Translational Medicine, Istanbul, Türkiye.
Department of Neurology, School of Medicine, Koç University, Istanbul, Turkey.
Exp Brain Res. 2025 May 4;243(6):138. doi: 10.1007/s00221-025-07085-w.
Recent studies in mouse models have demonstrated that ketamine and rapastinel induce rapid-acting and sustained antidepressant effects in major depressive disorder (MDD). However, it remains unclear how ketamine's and rapastinel's opposing mechanisms of action-NMDAR antagonist and NMDAR positive allosteric modulator, respectively-result in similar antidepressant-like effects. Furthermore, although the CaMKII/CREB pathway plays a crucial role in BDNF synthesis and synaptic plasticity, its involvement in rapastinel- or ketamine-induced antidepressant effects has not been studied in detail. The main purpose of this study was to analyze the link between BDNF levels and CaMKII/CREB activity in the antidepressant-like effects of rapastinel and ketamine treatments. This study used 46 male mice subjected to the chronic unpredictable mild stress (CUS) model for 28 days. Based on their experimental groups, the animals were administered the CaMKII inhibitor TatCN21 (5 mg/kg i.p.), ketamine (10 mg/kg i.p.), or rapastinel (3 mg/kg i.p.), either alone or in combination. Behavioral tests and molecular analyses were performed. The CUS model significantly reduced weight gain, decreased sucrose preference in the sucrose preference test (SPT), and increased immobility time in the forced swim test (FST) compared to the control group. BDNF concentrations in the prefrontal cortex (PFC) and hippocampus were significantly reduced following chronic stress. Both ketamine and rapastinel reduced anhedonia and passive coping behavior, demonstrating their antidepressant-like effects. Treatment with ketamine or rapastinel after chronic stress significantly increased BDNF concentrations in the PFC and hippocampus 24 h post-injection. Similarly, TatCN21 significantly increased BDNF levels in the PFC and hippocampus and reduced immobility time in the FST. Interestingly, when the CaMKII inhibitor was administered before ketamine or rapastinel, it had opposing effects on their antidepressant-like actions. TatCN21 enhanced rapastinel's effects while blocking the antidepressant-like effects of ketamine, suggesting that the CaMKII pathway may play a differential role in mediating these effects. Overall, this study provides insights into the potential mechanisms underlying the antidepressant-like effects of ketamine and rapastinel. Understanding these mechanisms could aid in developing new treatments for depression that are both rapid-acting and long-lasting, without the side effects associated with current medications.
最近在小鼠模型中的研究表明，氯胺酮和瑞帕斯汀在重度抑郁症（MDD）中可诱导快速起效且持久的抗抑郁作用。然而，目前尚不清楚氯胺酮和瑞帕斯汀相反的作用机制——分别为NMDAR拮抗剂和NMDAR正性变构调节剂——如何导致相似的抗抑郁样效果。此外，尽管CaMKII/CREB通路在脑源性神经营养因子（BDNF）合成和突触可塑性中起关键作用，但其在瑞帕斯汀或氯胺酮诱导的抗抑郁作用中的参与情况尚未得到详细研究。本研究的主要目的是分析BDNF水平与CaMKII/CREB活性在瑞帕斯汀和氯胺酮治疗的抗抑郁样作用中的联系。本研究使用了46只雄性小鼠，使其接受28天的慢性不可预测轻度应激（CUS）模型。根据实验组的不同，单独或联合给予动物CaMKII抑制剂TatCN21（5mg/kg腹腔注射）、氯胺酮（10mg/kg腹腔注射）或瑞帕斯汀（3mg/kg腹腔注射）。进行了行为测试和分子分析。与对照组相比，CUS模型显著降低了体重增加，降低了蔗糖偏好试验（SPT）中的蔗糖偏好，并增加了强迫游泳试验（FST）中的不动时间。慢性应激后，前额叶皮质（PFC）和海马中的BDNF浓度显著降低。氯胺酮和瑞帕斯汀均减轻了快感缺失和被动应对行为，显示出它们的抗抑郁样作用。慢性应激后注射氯胺酮或瑞帕斯汀显著增加了注射后24小时PFC和海马中的BDNF浓度。同样，TatCN21显著增加了PFC和海马中的BDNF水平，并减少了FST中的不动时间。有趣的是，当在氯胺酮或瑞帕斯汀之前给予CaMKII抑制剂时，它对它们的抗抑郁样作用有相反的影响。TatCN21增强了瑞帕斯汀的作用，同时阻断了氯胺酮的抗抑郁样作用，这表明CaMKII通路在介导这些作用中可能起不同的作用。总体而言，本研究为氯胺酮和瑞帕斯汀抗抑郁样作用的潜在机制提供了见解。了解这些机制有助于开发新的抑郁症治疗方法，这些方法起效快且持久，且无当前药物相关的副作用。
