Oizumi Hiroaki, Miyazaki Shinji, Tabuchi Masahiro, Endo Toshihiro, Omiya Yuji, Mizoguchi Kazushige
Tsumura Kampo Research Laboratories, Tsumura & Co., Ibaraki, Japan.
Phenovance Research & Technology, LLC, Chiba, Japan.
Front Pharmacol. 2020 Jul 17;11:1037. doi: 10.3389/fphar.2020.01037. eCollection 2020.
The cognitive and psychological domains of frailty in the elderly have drawn increasing attention given the aging of society. However, therapeutics to treat minor deficits in cognition and mental state in the elderly remain an unmet need. Kamikihito (KKT), a traditional Japanese Kampo medicine indicated for neuroses, anxiety, and insomnia, is effective for treating cognitive dysfunction and depressive-like behaviors in animal models, suggesting that it may have therapeutic potential for treating cognitive and/or mental frailty. In this study, we first validated the known anxiolytic effects of KKT in a conventional maze test. We then introduced an automated behavioral assay system, IntelliCage, to evaluate the therapeutic potential of KKT for age-related and diverse central functions by performing sequential behavioral tasks in young and aged mice to assess basal activities, cognitive functions, perseveration, and hedonic-related behaviors. Although young mice treated with KKT did not exhibit changes in diurnal variation, KKT-administered aged mice exhibited an accelerated decline in voluntary activity during the early part of the light period, implying that KKT may promote sleep onset in aged mice. Neither place learning acquisition for gaining rewards nor subsequent behavioral flexibility performance was altered by KKT in the young group, whereas the aged KKT group exhibited significantly enhanced performance in both phases of learning relative to age-matched controls. Conversely, perseverative nose-pokes (NPs) to gain rewards observed during place learning, indicative of compulsivity, were attenuated by KKT in both age groups. Regarding hedonic processing, aged mice exhibited a decreased preference for sweet solutions compared to young mice, which was effectively reversed by KKT treatment. Furthermore, KKT elevated high-effort choices for high-value reward in an effort-based decision-making paradigm in both age groups, implying augmentation of motivational behaviors by KKT. Collectively, KKT exerted various beneficial effects in cognitive and emotional domains, several of which were more evident in aged mice than in young mice, suggesting the potential of KKT for treating cognitive and mental frailty.
鉴于社会老龄化，老年人虚弱的认知和心理领域已引起越来越多的关注。然而，治疗老年人认知和精神状态轻微缺陷的疗法仍然存在未满足的需求。加味归脾汤（KKT）是一种用于治疗神经症、焦虑和失眠的传统日本汉方药物，在动物模型中对治疗认知功能障碍和抑郁样行为有效，表明它可能具有治疗认知和/或精神虚弱的潜力。在本研究中，我们首先在传统迷宫试验中验证了KKT已知的抗焦虑作用。然后，我们引入了一个自动化行为分析系统IntelliCage，通过在年轻和老年小鼠中执行一系列行为任务来评估KKT对与年龄相关的各种中枢功能的治疗潜力，以评估基础活动、认知功能、持续性和享乐相关行为。虽然用KKT治疗的年轻小鼠在昼夜变化上没有表现出变化，但给予KKT的老年小鼠在光照期早期自愿活动加速下降，这意味着KKT可能促进老年小鼠的睡眠开始。在年轻组中，KKT既没有改变获取奖励的位置学习能力获取，也没有改变随后的行为灵活性表现，而老年KKT组在学习的两个阶段相对于年龄匹配的对照组都表现出显著增强的表现。相反，在位置学习期间观察到的为获取奖励而进行的持续性鼻戳（NP），这表明存在强迫性，在两个年龄组中都被KKT减弱。关于享乐加工，与年轻小鼠相比，老年小鼠对甜味溶液的偏好降低，而KKT治疗有效地逆转了这种情况。此外，在基于努力的决策范式中，KKT提高了两个年龄组对高价值奖励的高努力选择，这意味着KKT增强了动机行为。总的来说，KKT在认知和情感领域发挥了各种有益作用，其中一些在老年小鼠中比在年轻小鼠中更明显，这表明KKT具有治疗认知和精神虚弱的潜力。
