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Memory Improvement by yokukansankachimpihange and Atractylenolide III in the Olfactory Bulbectomized Mice

Advances in Alzheimer's Disease 2016年第2期5卷 35-45页

作者： Hisanao Izumi Yuzuru Sasaki Yasushi Yabuki Yasuharu Shinoda Nina Fujita Satoshi Yomoda Kohji Fukunaga Department of Pharmacology Tohoku University Graduate School of Pharmaceutical Sciences Sendai Japan Department of Pharmacology Kampo Research Laboratories Kracie Pharma Ltd. Toyama Japan

Alzheimer’s Disease (AD) shows cognitive dysfunction as core symptoms and Behavioral and Psychological Symptoms of Dementia (BPSD). Since acetylcholine nerve system derived from septum is collapsed in the AD patients, we have used Olfactory Bulbectomized (OBX) mice whose cholinergic system is largely impaired in the septum. Recently, yokukansankachimpihange (YKH), a traditional Japanese Kampo medicine has used for BPSD in addition to improve cognitive dysfunction in AD patients. However the essential components for cognition and BPSD improvement and their mechanism are largely unknown. In present study, we found that Atractylenolide III (Aen-III), one of the components of YKH, improved cognitive deficits and depression in the OBX mice. OBX mice were orally administered with Aen-III (1.0 and 3.0 mg/kg) and YKH extracts daily for 18 days. Like YKH extracts, the Aen-III treatments ameliorated cognitive deficits and depression-like behavior observed in OBX mice. Importantly, Aen-III administration significantly restored the decreases in Ca2+/calmodulin-dependent protein kinase II (CaMKII) autophosphorylation and phosphorylation of Ca2+/calmodulin-dependent protein kinase IV (CaMKIV) and cyclic AMP response element binding protein (CREB). The restoration of CaMKII and CaMKIV signaling is closely related to the increased BDNF levels. Furthermore, ATP reduction in OBX mice was rescued by Aen-III (3.0 mg/kg) and YKH (1000 mg/kg) treatment. In summary, Aen-III as a component of YKH ameliorates cognitive dysfunctions and depression via restoring CaMKII and CaMKIV signaling.

关键词： yokukansankachimpihange Atractylenolide III Olfactory Bulbectomized Mice CaMKII BDNF

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The Efficacy and Safety of yokukansankachimpihange for Treating Behavioral and Psychological Symptoms of Dementia in Patients with Alzheimer’s Disease: An Open-Label Pilot Study

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Advances in Alzheimer's Disease 2018年第4期7卷 141-152页

作者： Ryutaro Arita Tetsuhiro Yoshino Miwako Ohgishi Takuya Hamaguchi Yuko Horiba Kaori Sawai Kei Funaki Hajime Tabuchi Mizuki Oka Takahito Yoshizaki Kenji Watanabe Masaru Mimura Center for Kampo Medicine School of Medicine Keio University Tokyo Japan Department of Neuropsychiatry School of Medicine Keio University Tokyo Japan Department of Neurology School of Medicine Keio University Tokyo Japan Faculty of Environmental and Information Study Keio University Fujisawa Japan

Previous clinical trials have demonstrated the efficacy of yokukansan, a traditional Japanese medicine, for the treatment of behavioral and psychological symptoms of dementia (BPSD). However, less evidence is available for the treatment of BPSD with yokukansankachimpihange (YKSCH), which consists of yokukansan and two additional herbal ingredients. The present study was conducted to investigate the efficacy and safety of YKSCH for treating BPSD in patients with Alzheimer’s disease (AD). We enrolled outpatients with mild-to-moderate AD who exhibited BPSD and obtained a Neuropsychiatric Inventory (NPI) score of >3 including subscale scores for “agitation”, “anxiety”, “irritability”, and “sleep and night-time behavior change”. A daily YKSCH dose of 7.5 g was administered for 12 weeks with concomitant administration of anti-dementia medication. BPSD was evaluated using the NPI at baseline and every 4 weeks during the intervention. We also examined apathy using the Japanese translation of the Apathy Scale, the short version of the Japanese version of the Zarit Caregiver Burden Interview, and the Modified Crichton Rating Scale for Predicting Activities of Daily Living. Cognitive dysfunction was evaluated using the Mini Mental State Examination and the AD Assessment Scale-Cognitive (Japanese version). Five participants were enrolled. The NPI total score tended to decrease between the baseline and 8-week evaluations during the YKSCH intervention (Wilcoxon signed rank test, P = 0.063). In terms of the NPI subscale scores, “apathy”, “agitation”, “delusions”, and “sleep and night-time behavior change” decreased after the intervention in those who exhibited each symptom at baseline. There were no significant differences in the other scores examined. No serious adverse events were observed. YKSCH could ameliorate BPSD in patients with mild-to-moderate AD with agitation, anxiety, irritability, and sleep and night-time behavior change, and it was well-tolerated.

关键词： Alzheimer’s Disease Behavioral and Psychological Symptoms of Dementia yokukansankachimpihange Kampo Medicine Apathy Neuropsychiatric Inventory

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