Traditional Japanese apricot (Prunus mume) induces osteocalcin in osteoblasts.

The fruit of Prunus mume (ume, also known as Japanese apricot) has been used as a functional food in Japan since ancient times. We previously reported that ume stimulates the differentiation of preosteoblastic cells. Osteocalcin (OCN) is secreted by osteoblasts, and there is known association with glucolipid metabolism and cognitive function. This study sought to clarify the relationship between ume extracts and OCN production both in vitro and in vivo. Alkaline phosphatase activity and OCN level in the ethyl acetate extracts of ume-treated extracts were significantly increased in preosteoblast MC3T3-E1 cells compared with the control group. In human study, serum OCN level was significantly higher in the high ume intake group than in the low intake group in community-dwelling participants over 60 years old. These results suggest that ume has the potential to upregulated OCN production both in vitro and in vivo.

Dietary Intake of Sulforaphane-Rich Broccoli Sprout Extracts during Juvenile and Adolescence Can Prevent Phencyclidine-Induced Cognitive Deficits at Adulthood.

Oxidative stress and inflammation play a role in cognitive impairment, which is a core symptom of schizophrenia. Furthermore, a hallmark of the pathophysiology of this disease is the dysfunction of cortical inhibitory γ-aminobutyric acid (GABA) neurons expressing parvalbumin (PV), which is also involved in cognitive impairment. Sulforaphane (SFN), an isothiocyanate derived from broccoli, is a potent activator of the transcription factor Nrf2, which plays a central role in the inducible expressions of many cytoprotective genes in response to oxidative stress. Keap1 is a cytoplasmic protein that is essential for the regulation of Nrf2 activity. Here, we found that pretreatment with SFN attenuated cognitive deficits, the increase in 8-oxo-dG-positive cells, and the decrease in PV-positive cells in the medial prefrontal cortex and hippocampus after repeated administration of phencyclidine (PCP). Furthermore, PCP-induced cognitive deficits were improved by the subsequent subchronic administration of SFN. Interestingly, the dietary intake of glucoraphanin (a glucosinolate precursor of SFN) during the juvenile and adolescence prevented the onset of PCP-induced cognitive deficits as well as the increase in 8-oxo-dG-positive cells and the decrease in PV-positive cells in the brain at adulthood. Moreover, the NRF2 gene and the KEAP1 gene had an epistatic effect on cognitive impairment (e.g., working memory and processing speed) in patients with schizophrenia. These findings suggest that SFN may have prophylactic and therapeutic effects on cognitive impairment in schizophrenia. Therefore, the dietary intake of SFN-rich broccoli sprouts during the juvenile and adolescence may prevent the onset of psychosis at adulthood.

Yokukansan and its ingredients as possible treatment options for schizophrenia.

Schizophrenia is a debilitating psychotic mental disorder that affects almost the entire range of human mental function. The devastating effect of the illness is usually long-lasting and requires lifelong treatment. Despite an evolved psychopharmacological understanding, the overall therapeutic effect of antipsychotics is still not satisfactory. The choice of proper medication presents a clinical dilemma between efficacy and safety. As a result, searching for comparable treatment options with safer profiles is very important. Yokukansan (TJ-54), also called yi-gan san in Chinese, is a traditional herbal medicine with evident therapeutic effect for neuropsychiatric disorders. There are several open-label clinical studies upholding the possibility of using yokukansan to treat schizophrenia or schizophrenia-like psychosis. Evidence from animal studies and neurobiology also sheds light on the antipsychotic implications of yokukansan and its ingredients. Nevertheless, correlations between the experimental environment and clinical settings may be complicated by a number of confounders. Clinical trials with more sophisticated designs are required to fill the gap between the experimental environment and clinical settings.

In vitro acetylcholinesterase inhibitory activity and the antioxidant properties of Aegle marmelos leaf extract: implications for the treatment of Alzheimer's disease.

BACKGROUND: Alzheimer's disease (AD) is a progressive neurodegenerative disorder clinically characterized by loss of memory and cognition. The effective therapeutic options for AD are limited and thus there is a demand for new drugs. Aegle marmelos (Linn.) (A. marmelos) leaves have been used in traditional medicine to promote intellect and enhance memory. In this study, we evaluated A. marmelos for its acetylcholinesterase (AChE) inhibitory activity and antioxidant property in vitro in the treatment of AD. METHODS: A crude methanol extract and four fractions (petroleum ether, chloroform, ethyl acetate and aqueous) were prepared from the leaves of A. marmelos. The preparations were assessed for AChE inhibitory activity by the Ellman method, and their antioxidant properties were assessed by several assays: reducing power, scavenging of 1,1-diphenyl-2-picrylhydrazyl free radical and hydroxyl radical, and inhibition of lipid peroxidation. Qualitative and quantitative analyses of endogenous substances in A. marmelos were performed by the standard phytochemical methods. RESULTS: Among the different extracts tested, the ethyl acetate fraction exhibited the highest inhibition of AChE activity. In the same way, ethyl acetate fraction showed the highest reducing activity and radical scavenging ability towards the 1,1-diphenyl-2-picrylhydrazyl (half maximal inhibitory concentration = 3.84 µg/mL) and hydroxyl free radicals (half maximal inhibitory concentration = 5.68 µg/mL). The antiradical activity of the ethyl acetate fraction appeared to be similar to that of the reference standard butylated hydroxytoluene and catechin used in this study. In addition, the ethyl acetate fraction displayed higher inhibition of brain lipid peroxidation. Phytochemical screening of different extractives of A. marmelos showed the presence of phenols and flavonoids, alkaloid, saponin, glycoside, tannin and steroids. Quantitative analysis revealed higher contents of phenolics (58.79-mg gallic acid equivalent/g dried extract) and flavonoids (375.73-mg gallic acid equivalent/g dried extract) in the ethyl acetate fraction. CONCLUSION: The results suggest that the ethyl acetate fraction of A. marmelos is a significant source of polyphenolic compounds with potential AChE inhibitory property and antioxidant activity and, thus, may be useful in the treatment of AD.

New possibility of traditional Chinese and Japanese medicine as treatment for behavioral and psychiatric symptoms in dementia.

Yokukansan, one of the Kampo prescriptions, is composed of seven herbaceous plants and was developed in China in the 16th century as a cure for restlessness and agitation in children. Yokukansan has also become a popular drug combination in Japan, especially for the behavioral and psychiatric symptoms of dementia (BPSD). Recent studies have shown that yokukansan might also be quite effective against BPSD occurring in association with other types of dementia, such as Alzheimer's disease, Lewy body disease, Parkinson's disease with dementia, frontotemporal dementia, and vascular dementia. Researchers have intensively investigated yokukansan, focusing on the pharmacological mechanisms against glutamate-mediated excitotoxicity. This traditional Chinese and Japanese medicine holds potential promise for improving BPSD in elderly patients suffering from dementia.

No associations found between the genes situated at 6p22.1, HIST1H2BJ, PRSS16, and PGBD1 in Japanese patients diagnosed with schizophrenia.

Recent GWAS demonstrated an association between candidate genes located at region 6p22.1 and schizophrenia. This region has been reported to house certain candidate SNPs, which may be associated with schizophrenia at HIST1H2BJ, PRSS16, and PGBD1. These genes may presumably be associated with pathophysiology in schizophrenia, namely epigenetics and psychoneuroimmunology. A three-step study was undertaken to focus on these genes with the following aims: (1) whether these genes may be associated in Japanese patients with schizophrenia by performing a 1st stage case-control study (514 cases and 706 controls) using Japanese tagging SNPs; (2) if the genetic regions of interest for the disease from the 1st stage of analyses were found, re-sequencing was performed to search for new mutations; (3) finally, a replication study was undertaken to confirm positive findings from the 1st stage were reconfirmed using a larger number of subjects (2,583 cases and 2,903 controls) during a 2nd stage multicenter replication study in Japan. Genotyping was performed using TaqMan PCR method for the selected nine tagging SNPs. Although three SNPs situated at the 3' side of PGBD1; rs3800324, rs3800327, and rs2142730, and two-window haplotypes between rs3800327 and rs2142730 showed positive associations with schizophrenia, these associations did not have enough power to sustain significance during the 2nd stage replication study. In addition, re-sequencing for exons 5 and 6 situated at this region did not express any new mutations for schizophrenia. Taken together these results indicate that the genes HIST1H2BJ, PRSS16, and PGBD1 were not associated with Japanese patients with schizophrenia.

Laughter and humor as complementary and alternative medicines for dementia patients.

BACKGROUND: The number of dementia patients has increased worldwide, with an estimated 13.7 million dementia patients in the Asia Pacific region alone. This number is expected to increase to 64.6 million by the year 2050. DISCUSSION: As a result of advances in research, there several pharmacological therapies available for the treatment of dementia patients. However, current treatments do not suppress the disease process and cannot prevent dementia, and it will be some time before these goals are realized. In the meantime, complementary and alternative medicine (CAM) is an important aspect in the treatment of dementia patients to improve their quality of life throughout the long course of the disease. Considering the individuality of dementia patients, applicability of laughter and humor therapy is discussed. Even though there are many things that need to be elucidated regarding the mechanisms underlying the beneficial effects of laughter and humor, both may be good CAM for dementia patients if they are applied carefully and properly. SUMMARY: In this debate article, the physiological basis and actual application of laughter and humor in the treatment of dementia patients are presented for discussion on the applicability to dementia patients.

Relationship between prepulse inhibition of acoustic startle response and schizotypy in healthy Japanese subjects.

Prepulse inhibition (PPI) of the acoustic startle reflex (ASR) is the most common psychophysiological index of sensorimotor gating. Several studies have investigated the relationship of PPI of ASR to schizotypy in Caucasians. However, little has been reported on this relationship in Asians. We investigated a possible relationship between PPI of ASR and schizotypy in 79 healthy Japanese subjects. Schizotypy was assessed by the Schizotypal personality Questionnaire (SPQ). PPI was evaluated at signal-to-noise ratios (SnRs: difference between background noise intensity and prepulse intensity) of +12, +16, and +20 dB. The total SPQ score, cognitive/perceptual score, and interpersonal score correlated negatively with PPI at SnR of +16 and +20 dB. We conclude that PPI is associated with the trait of schizotypy in healthy Asian subjects.

Prepulse inhibition of the startle response with chronic schizophrenia: a replication study.

Prepulse inhibition (PPI) deficit, the acoustic startle reflex (ASR) and habituation (HAB) impairment are considered to be endophenotypes for schizophrenia. The recent two studies have reported that a PPI deficit was detected in Japanese schizophrenic patients. We replicated that study using larger samples (115 schizophrenic patients and 111 normal controls) than the original study and a method same as original study. A startle response monitoring system was used to deliver acoustic startle stimuli, and to record and score the electromyographic activity of the orbicularis oculi muscle. We evaluated the startle measures of mean magnitude of ASR, HAB, and PPI at prepulse sound pressure intensities of 82dB (PPI82), 86dB (PPI86), and 90dB (PPI90). ASR was significantly different between schizophrenic patients and controls. HAB and all PPI session data from schizophrenic patients were significantly lower than in controls. In addition, we detected significant differences for ASR, HAB and each PPI (82, 86 and 90dB) between schizophrenic patients and controls with the use of multiple regression analysis. The gender and smoking state were not correlated with ASR, HAB or any PPI in multiple regression analysis. In conclusion, we were able to replicate the finding of HAB impairment and PPI deficit in chronic Japanese schizophrenic patients.

Cortical oscillatory power changes during auditory oddball task revealed by spatially filtered magnetoencephalography.

OBJECTIVE: To investigate the neural sources and associated changes in oscillatory activity involved in auditory attention and memory updating processing using spatially filtered magnetoencephalography. METHODS: We recorded magnetic responses during an auditory oddball task in 12 normal subjects. Synthetic aperture magnetometry (SAM)-permutation analysis was used to visualize the multiple brain regions associated with event-related magnetic fields (ERFs), and event-related oscillations during target detection processing. RESULTS: SAM-permutation results showed the topographical distribution of N1m over the bilateral primary auditory cortex. Post-stimulus delta (1.5-4 Hz) activity sources, likely related to the P300 slow-waveform, were distributed over the right frontocentral and parietal regions. Source locations of theta (4-8 Hz) and alpha (8-13 Hz) event-related synchronization (ERS) were identified over the dorsolateral and medial prefrontal cortex. We visualized bilateral central-Rolandic suppresions for mu (8-15 Hz), beta (15-30 Hz), and low-gamma (30-60 Hz) activities, more dominant in the hemisphere contralateral to the moving hand (button-pressing in response to target stimuli). CONCLUSIONS: Prefrontal theta and alpha ERS, and frontocentral-parietal delta ERS are functionally engaged in auditory attention and memory updating process. SIGNIFICANCE: Spatially filtered MEG is valuable for detection and source localization of task-related changes in the ongoing oscillatory activity during oddball tasks.

Impaired prepulse inhibition and habituation of acoustic startle response in Japanese patients with schizophrenia.

Prepulse inhibition (PPI) and habituation of the acoustic startle reflex (ASR) are considered to be candidate endophenotypes of schizophrenia. However, to our knowledge, only one group has investigated these startle measures in Asian patients with schizophrenia. In the present study, we evaluated these startle measures in 51 Japanese patients with schizophrenia and compared them with those of 55 healthy age- and sex-matched Japanese controls. A human startle response monitoring system was used to deliver acoustic startle stimuli, and record and score the electromyographic activity of the orbicularis oculi muscle. The startle measures examined were mean magnitude of ASR to pulse alone trials in initial block (SR), habituation of ASR during the session (HAB), and PPI at prepulse intensities of 82 dB (PPI82), 86 dB (PPI86), and 90 dB (PPI90) sound pressure level. SR was not significantly different between the patients and controls. Patients displayed significantly reduced HAB and PPI for all prepulse intensities compared to controls. The greatest statistical difference in PPI between patients and controls was found with PPI86. This did not correlate with any clinical variable in each group. Our results indicate that PPI and habituation of ASR are impaired in Asian patients with schizophrenia.

Donepezil in the treatment of musical hallucinations.

Musical hallucinations (MH) typically occur among elderly individuals and are associated with hearing impairment. The authors describe a patient with features of typical MH who was successfully treated with donepezil, a cholinesterase inhibitor, as a combination therapy and who has not shown any subsequent cognitive decline for approximately 5 years. The efficacy of donepezil in this patient indicates that age-dependent dysfunction of cholinergic neurons might be related to the development of MH.

Effectiveness of a clinical pathway for the diagnosis and treatment of dementia and for the education of families.

AIMS: Clinical pathways (CPs) are rarely used in the treatment of dementia. We established a CP for a series of medical practices (diagnosis, treatment, establishment of a care system, and caregiver education) for patients with dementia hospitalized for a three-week period, and evaluated its usefulness. METHODS: The length of hospital stay and hospital costs were compared between 23 consecutive patients with dementia hospitalized and treated using a CP and 20 controls treated by conventional medical practice without using a CP in a special ward for dementia patients. In the CP group, at the time of discharge, primary caregivers, physicians, and nurses were given a questionnaire to obtain their comments about the impression of treatment with the CP. RESULTS: The questionnaire survey indicated that the CP deepened the caregiver's understanding of the sequence of medical practices for the inpatient, the disorders of the inpatient, the treatment methods, and the methods for coping with the disorder. The CP was also useful for facilitating inpatient medical practice and promoting the establishment of a care system after discharge. The use of the CP significantly shortened the length of hospital stay and decreased hospital costs during hospitalization but increased the amount of work per day and made the medical staff feel that their freedom to choose medical procedures had been restricted. CONCLUSIONS: The CP was useful for execution of inpatient medical practices for patients with dementia.

Slow repetitive transcranial magnetic stimulation increases somatosensory high-frequency oscillations in humans.

Repetitive transcranial magnetic stimulation (rTMS) has been proposed as a possible treatment for psychiatric and neurological disorders characterized by focal brain excitability, such as major depression and action myoclonus. However, the mechanism of modulating excitability by rTMS is unclear. We examined the changes in high frequency oscillations (HFOs) of somatosensory evoked potentials (SEPs) before and after slow rTMS over the right primary somatosensory cortex (0.5 Hz, 50 pulses, 80% motor threshold intensity). The HFOs, which represent a localized activity of intracortical inhibitory interneurons, were significantly increased after slow rTMS, while the SEPs were not changed. Our results suggest that slow rTMS affects cortical excitability by modulating the activity of the intracortical inhibitory interneurons beyond the time of the stimulation and that rTMS may have therapeutic effects on such disorders.

MEG study of long-term cortical reorganization of sensorimotor areas with respect to using chopsticks.

The movements required to use chopsticks are overlearned and routine in Asians. Most non-Asians, on the other hand, typically have difficulty performing this unfamiliar manual activity, and have to focus their attention on the movements required to use chopsticks adequately. Using magnetoencephalography (MEG) we compared the cortical activation of highly trained Asian chopstick users to the activation of Europeans who only occasionally used chopsticks, while they performed the same tasks with chopsticks or a control task of simple tapping of the same fingers. The data were analyzed using the new method of synthetic aperture magnetometry (SAM). In Europeans there was a significantly higher ratio of spectral power in the higher gamma frequency band (60-80 Hz) over the sensorimotor area compared to the Asian subjects. From these results we conclude that the high gamma band activity in the sensorimotor area may reflect focused attention and functional reorganization of the cortical network with respect to sensorimotor experience.