Koh Iwasaki

Uncaria rhynchophylla, a Chinese medicinal herb, has potent antiaggregation effects on Alzheimer's β‐amyloid proteins

Because the deposition of β‐amyloid protein (Aβ) is a consistent pathological hallmark of Alzheimers disease (AD) brains, inhibition of Aβ generation, prevention of Aβ fibril formation, or destabilization of preformed Aβ fibrils would be attractive therapeutic strategies for the treatment of AD. We examined the effects of several medicinal herbs used in traditional Chinese medical formulae on the formation and destabilization of Aβ fibrils by using the thioflavin T binding assay, atomic force microscopic imaging, and electrophoresis. Our study demonstrates that several of these herbs have potent inhibitory effects on fibril formation of both Aβ1–40 and Aβ1–42 in concentration‐dependent manners; in particular, Uncaria rhynchophylla inhibited Aβ aggregation most intensively. Significant destabilization of preformed Aβ1–40 and Aβ1–42 fibrils was also induced by Uncaria rhynchophylla as well as some other herb extracts. Three‐dimensional HPLC analysis indicated that the water extract of this herb contains several different chemical compounds, including oxindole and indol alkaloids, which have been regarded as neuroprotective. Our results suggest that Uncaria rhynchophylla has remarkably inhibitory effects on the regulation of Aβ fibrils, and we conclude that this medicinal herb could have the potency to be a novel therapeutic agent to prevent and/or cure AD.

A traditional medicinal herb Paeonia suffruticosa and its active constituent 1,2,3,4,6‐penta‐O‐galloyl‐β‐d‐glucopyranose have potent anti‐aggregation effects on Alzheimer’s amyloid β proteins in vitro and in vivo

The deposition of amyloid β (Aβ) protein is a consistent pathological hallmark of Alzheimer’s disease (AD) brains; therefore, inhibition of Aβ fibril formation and destabilization of pre‐formed Aβ fibrils is an attractive therapeutic and preventive strategy in the development of disease‐modifying drugs for AD. This study demonstrated that Paeonia suffruticosa, a traditional medicinal herb, not only inhibited fibril formation of both Aβ1–40 and Aβ1–42 but it also destabilized pre‐formed Aβ fibrils in a concentration‐dependent manner. Memory function was examined using the passive‐avoidance task followed by measurement of Aβ burden in the brains of Tg2576 transgenic mice. The herb improved long‐term memory impairment in the transgenic mice and inhibited the accumulation of Aβ in the brain. Three‐dimensional HPLC analysis revealed that a water extract of the herb contained several different chemical compounds including 1,2,3,4,6‐penta‐O‐galloyl‐β‐d‐glucopyranose (PGG). No obvious adverse/toxic were found following treatment with PGG. As was observed with Paeonia suffruticosa, PGG alone inhibited Aβ fibril formation and destabilized pre‐formed Aβ fibrils in vitro and in vivo. Our results suggest that both Paeonia suffruticosa and its active constituent PGG have strong inhibitory effects on formation of Aβ fibrils in vitro and in vivo. PGG is likely to be a safe and promising lead compound in the development of disease‐modifying drugs to prevent and/or cure AD.

Yokukansan, a traditional Japanese medicine, ameliorates memory disturbance and abnormal social interaction with anti-aggregation effect of cerebral amyloid β proteins in amyloid precursor protein transgenic mice.

The deposition of amyloid β protein (Aβ) is a consistent pathological hallmark of Alzheimers disease (AD) brains. Therefore, inhibition of Aβ aggregation in the brain is an attractive therapeutic and preventive strategy in the development of disease-modifying drugs for AD. An in vitro study demonstrated that yokukansan (YKS), a traditional Japanese medicine, inhibited Aβ aggregation in a concentration-dependent manner. An in vivo study demonstrated that YKS and Uncaria hook (UH), a constituent of YKS, prevented the accumulation of cerebral Aβ. YKS also improved the memory disturbance and abnormal social interaction such as increased aggressive behavior and decreased social behavior in amyloid precursor protein transgenic mice. These results suggest that YKS is likely to be a potent and novel therapeutic agent to prevent and/or treat AD, and that this may be attributed to UH.

The traditional Chinese medicine banxia houpo tang improves swallowing reflex.

A marked depression of swallowing reflex has been found in patients with aspiration pneumonia. We have examined the effects of Banxia Houpo Tang (BHT, Hange Koboku-To in Japanese), on swallowing reflex among the elderly. Thirty-two patients, mean age 74.2 +/- 1.7 years who had at least one episode of aspiration pneumonia, were divided into two groups. Twenty patients took BHT extracts of 7.5 g per day for four weeks, and the other 12 patients took a placebo. The swallowing reflex was measured by a bolus injection of 1 ml of distilled water into the pharynx through a nasal catheter. The reflex was evaluated by the latency time of response, which was the time from the injection to the onset of swallowing. The latency of response decreased significantly from 11.6 +/- 3.0 sec to 2.6 +/- 0.4 sec in the group treated with BHT (p < 0.01), while in the other group with placebo it was from 11.0 +/- 4.0 to 10.8 +/- 3.6 (p > 0.5). Depletion of substance P in the pharynx causes impairments of the swallowing reflex. Substance P in the saliva of treated patients increased from 9.2 +/- 2.5 fmol/ml to 15.0 +/- 2.2 fmol/ml after BHT treatment (p < 0.01), while levels were 8.0 +/- 4.0 fmol/ml before and 7.1 +/- 3.1 fmol/ml after among the placebo group (no significant difference). We suggest that BHT improves the impaired swallowing reflex and may help to prevent aspiration pneumonia in the elderly.

A Pilot Study of Banxia Houpu Tang, a Traditional Chinese Medicine, for Reducing Pneumonia Risk in Older Adults with Dementia

OBJECTIVES: To evaluate whether the traditional Chinese herbal medicine Banxia Houpu Tang (BHT, formula magnolia et pinelliae) prevents aspiration pneumonia and pneumonia‐related mortality in elderly people.

Improvement in delusions and hallucinations in patients with dementia with Lewy bodies upon administration of yokukansan, a traditional Japanese medicine.

Background:  This multicentre open‐label trial examined the efficacy and safety of the traditional Japanese medicine, or Kampo medicine, yokukansan (YKS), for behavioural and psychological symptoms of dementia (BPSD) in patients with dementia with Lewy bodies.

Dementia caregivers’ burdens and use of public services

Background:  The objectives of the present study are to examine risk factors for the heavy burden of caring for demented patients as well as factors that may affect on the level of utilization by carers of public services under current long‐term care insurance in Japan.

The effects of the traditional Chinese medicine, "Banxia Houpo Tang (Hange-Koboku To)" on the swallowing reflex in Parkinson's disease.

Swallowing disorder is common in Parkinsons disease (PD). We studied the swallowing disorder in PD, and tested the efficacy of Banxia Houpo Tang (BHT, a Chinese traditional medicine) in improving the swallowing reflex of PD patients. The Swallowing reflex test is a simple method used to detect swallowing disorders in patients with cerebrovascular disease. Because we observed previously that BHT significantly improved the swallowing reflex in cerebrovascular patients, we studied whether BHT was also effective in improving the swallowing disorder in patients with PD. 23 PD patients (13 males, 10 females, mean age 66.0+/-9.3, Hoehn & Yahr (H-Y) mean score = 2.8) were evaluated for swallowing reflex and the concentration of substance-P in their saliva before and after 4 weeks of BHT treatment. The swallowing reflex before treatment was significantly delayed, according to the H-Y score (Spearmans p = 0.014, R2 = 0.463). The swallowing reflex before BHT treatment was 3.66+/-0.98 sec, and after BHT treatment, it improved significantly, to 2.27+/-0.54 sec (p < 0.0001). Substance-P concentration in PD patients saliva before treatment was significantly lower than in healthy controls (p = 0.007), but showed no significant change after BHT treatment. Our research shows that the swallowing reflex is an effective method to evaluate the swallowing disorder in PD. BHT can significantly improved the swallowing reflex in PD patients, and therefore can be a hopeful candidate for preventing aspiration pneumonia in PD.

Dietary patterns associated with fall-related fracture in elderly Japanese: a population based prospective study

BackgroundDiet is considered an important factor for bone health, but is composed of a wide variety of foods containing complex combinations of nutrients. Therefore we investigated the relationship between dietary patterns and fall-related fractures in the elderly.MethodsWe designed a population-based prospective survey of 1178 elderly people in Japan in 2002. Dietary intake was assessed with a 75-item food frequency questionnaire (FFQ), from which dietary patterns were created by factor analysis from 27 food groups. The frequency of fall-related fracture was investigated based on insurance claim records from 2002 until 2006. The relationship between the incidence of fall-related fracture and modifiable factors, including dietary patterns, were examined. The Cox proportional hazards regression model was used to examine the relationships between dietary patterns and incidence of fall-related fracture with adjustment for age, gender, Body Mass Index (BMI) and energy intake.ResultsAmong 877 participants who agreed to a 4 year follow-up, 28 suffered from a fall-related fracture. Three dietary patterns were identified: mainly vegetable, mainly meat and mainly traditional Japanese. The moderately confirmed (see statistical methods) groups with a Meat pattern showed a reduced risk of fall-related fracture (Hazard ratio = 0.36, 95% CI = 0.13 - 0.94) after adjustment for age, gender, BMI and energy intake. The Vegetable pattern showed a significant risk increase (Hazard ratio = 2.67, 95% CI = 1.03 - 6.90) after adjustment for age, gender and BMI. The Traditional Japanese pattern had no relationship to the risk of fall-related fracture.ConclusionsThe results of this study have the potential to reduce fall-related fracture risk in elderly Japanese. The results should be interpreted in light of the overall low meat intake of the Japanese population.

BENEFITS OF COMBINING DONEPEZIL PLUS TRADITIONAL JAPANESE HERBAL MEDICINE ON COGNITION AND BRAIN PERFUSION IN ALZHEIMER'S DISEASE: A 12-WEEK OBSERVER-BLIND, DONEPEZIL MONOTHERAPY CONTROLLED TRIAL

To the Editor: Although many attempts have been made to demonstrate its cognitive benefits in Alzheimer’s disease (AD), donepezil, one of the cholinesterase (ChE) inhibitors, is still a standard therapeutic agent. Because of a limited benefit of a single drug alone, several clinical trials of combination regimen have been reported. One study demonstrated that an inhibition of ChE leads to a marked reduction of choline acetyltransferase (ChAT) levels in the rat brain. A negative feedback mechanism may explain this finding, supporting the use of a ChAT activator in combination with donepezil in AD. Kami-Untan-To (KUT), a traditional Japanese herbal medicine, is known to upregulate the expression of ChAT at the messenger ribonucleic acid level. It also increases acetylcholine levels and the number of ChAT-positive neurons in aged mice. Finally, Suzuki et al. conducted a clinical trial of KUT to evaluate safety and efficacy in patients with mild to moderate AD. Therefore, we designed an observer-blind, donepezil monotherapy controlled clinical trial of a combination of donepezil plus KUT. A 12-week, observer-blind, donepezil monotherapy controlled clinical trial was conducted at the Tohoku University hospital outpatient clinic for dementia from October 2003 through January 2005. Thirty-eight eligible AD patients (National Institute of Neurological and Communicative Disorders and StrokeFAlzheimer’s Disease and Related Disorders Association criteria) were randomly assigned to receive donepezil alone (n 5 20, mean age standard deviation 74.6 3.9; men, n 5 4; women n 5 16) or a combination of donepezil and KUT (n 5 18, aged 73.7 5.6; men, n 5 4; women n 5 14). In both groups, patients received a 3-mg daily dose of donepezil for the first 14 days followed by an escalation to 5 mg thereafter. The 13 herbs of KUT were purchased from Tsumura Co. Ltd, Tokyo, Japan. The quality of the herbs was standardized based on the Good Manufacturing Practice defined by the Ministry of Health and Welfare of Japan. Cognitive function was measured using the Alzheimer’s Disease Assessment Scale-cognitive subscale (ADAS-cog) and Mini-Mental State Examination (MMSE), as well as regional cerebral blood flow (rCBF) using I-IMP-ARG single photon emission computed tomography, with SPM99 software package (Wellcome Department of Imaging Neuroscience, London, UK) implemented in MATLAB 5.3 system (Mathworks Inc., Natick, MA). At baseline, there was no significant difference in age, sex distribution, MMSE score (19.6 4.1 vs 18.9 4.9 points), ADAS-cog score (19.5 6.8 vs 21.0 7.6 points), prevalence of silent brain infarction (38% vs 44%), or grade for deep white matter lesions (0.9 0.6 vs 1.1 0.2) and for periventricular hyperintensity (0.7 0.8 vs 0.7 0.8) (as previously defined) between the treatment groups (chi-square test, P4.05). Two patients in the donepezil monotherapy group had intractable diarrhea, conceivably due to cholinergic adverse effects by donepezil. No such event was observed in the combination group. Analyses were performed using the last observation carried forward method. Differences in the MMSE and ADAScog scores between baseline and posttreatment were analyzed using a paired t test and repeated measure analysis of variance. As shown in Figure 1A, relative to baseline, posttreatment MMSE scores significantly improved only in the combination group (from 18.9 4.9 to 21.6 4.2 points, P 5.001; 4.17o95% confidence interval (CI) o 1.28) but not in the donepezil monotherapy group (from 19.6 4.1 to 20.4 4.5). As shown in Figure 1B, ADAScog scores also improved significantly in the combination group (from 21.0 7.6 to 16.8 7.1, Po.001; 2.54o 95% CIo5.80) but not in the monotherapy group (from 19.5 6.8 to 18.2 7.0). Furthermore, as shown in Figure 1C, the rCBF in frontal regions significantly increased in the combination group alone (Po.05 corrected: Brodmann’s area (BA) 9, (x, y, z) 5 (8, 50, 24), Z 5 5.19; BA 8, (x, y, z) 5 (26, 28, 46), Z 5 5.04; BA 9, (x, y, z) 5 (8, 54, 36), Z 5 4.99; kE 5 6,029). Despite a small sample size and a short observation period, we demonstrated that the combined use of donepezil plus KUT was more beneficial than donepezil alone in cognition and brain perfusion. Although cholinergicrelated adverse effects might be expected, such events did not occur in the combination group. Therefore, it is likely that donepezil and KUT worked synergistically in a safe fashion to enhance availability of acetylcholine. In our study, the prevalence of silent brain infarction was 38% in the donepezil monotherapy group and 44% in the combination group. This was comparable with results of studies with serially enrolled autopsy-confirmed AD cases by Heyman et al. (30.2%). Therefore, it should be noted that our study was conducted in a mixed population of pure AD and AD with cerebrovascular diseases. In summary, KUT might be used as a complementary regimen to enhance treatment success of current cholinergic therapy for AD.