Li Ling, Zhang Zhiting, Liu Xinhe, Zhou Mengni, Wen Shenglin, Dai Ji
Department of Psychology, The Fifth Affiliated Hospital, Sun Yat-Sen University, Zhuhai 519000, China.
Shenzhen Technological Research Center for Primate Translational Medicine, Shenzhen-Hong Kong Institute of Brain Science, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518055, China.
Biomedicines. 2025 Jun 5;13(6):1389. doi: 10.3390/biomedicines13061389.
Major Depressive Disorder represents a prevalent and critical mental health issue that highlights the pressing need for innovative therapeutic solutions. Recent research has identified dysfunction within the glutamate system as a crucial element influencing both the onset and management of depressive symptoms. Although TAK-653 is a new positive allosteric modulator of AMPA receptors, its effects have not been rigorously examined in models of depression in primates. To assess its potential antidepressant properties, a chronic unpredictable mild stress protocol was implemented over 12 weeks to create a monkey model of depression, followed by a two-week treatment period with TAK-653. Behavioral evaluations showed that following stress exposure, the monkeys exhibited reduced motivation for food, increased huddling, diminished movement, and a tendency to remain at the lower levels of their enclosure. They also displayed heightened anxiety in response to external stimuli. Plasma analyses indicated higher levels of cortisol, IL-6, and IL-8 in the stressed monkeys compared to baseline readings, confirming the efficacy of the stress-inducing protocol. Post-treatment with TAK-653 resulted in significant improvements, such as enhanced motivation for food, less huddling behavior, greater activity, and a move towards the upper areas of the enclosure. Additionally, the plasma analysis revealed a marked decrease in cortisol and IL-6 levels, along with an increased expression of BDNF. These findings indicate that TAK-653 effectively alleviates depression-like behaviors in nonhuman primate models, thereby paving the way for a promising new strategy in the treatment of depression.
重度抑郁症是一个普遍且严重的心理健康问题，凸显了对创新治疗方案的迫切需求。最近的研究已确定谷氨酸系统功能失调是影响抑郁症状发作和管理的关键因素。尽管TAK-653是一种新型的AMPA受体正向变构调节剂，但其在灵长类动物抑郁症模型中的作用尚未得到严格检验。为了评估其潜在的抗抑郁特性，实施了为期12周的慢性不可预测轻度应激方案以建立抑郁症猴子模型，随后用TAK-653进行为期两周的治疗期。行为评估表明，在应激暴露后，猴子表现出对食物的动机降低、蜷缩增加、活动减少以及倾向于待在笼子较低位置。它们对外界刺激的焦虑也有所增加。血浆分析表明，与基线读数相比，应激猴子体内的皮质醇、IL-6和IL-8水平更高，证实了应激诱导方案的有效性。用TAK-653治疗后有显著改善，如对食物的动机增强、蜷缩行为减少、活动增加以及向笼子上部区域移动。此外，血浆分析显示皮质醇和IL-6水平显著降低，同时脑源性神经营养因子（BDNF）表达增加。这些发现表明TAK-653能有效减轻非人类灵长类动物模型中的抑郁样行为，从而为抑郁症治疗开辟了一种有前景的新策略。
