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Behavioral and psychological symptoms of dementia (BPSD), including anxiety, depression, excitement, anger, hallucination, and roaming, are seen in patients with Alzheimer's disease and other forms of senile dementia. 1,2) To date, although atypical or conventional antipsychotic medications are used to treat BPSD, drug-induced extrapyramidal symptoms and other adverse events are seen. In addition, the Food and Drug Administration warned in 2005 that the antipsychotic medications increase mortality among elderly patients. Therefore, new remedies without adverse effects have been sought.Yokukansan (TJ-54) is a traditional herbal medicine called a 'kampo medicine' in Japan. The Ministry of Health, Labor and Welfare in Japan has approved it as a remedy for neurosis, insomnia, and irritability in children. Recently, TJ-54 has been reported to ameliorate excitement, anger, and hallucination in BPSD in patients with Alzheimer's disease, dementia with Lewy bodies, and other forms of senile dementia. 1,2) However, there is limited research on this compound and the mechanism by which it alters the symptoms of dementia is unknown.Up to now, various dementia models including b-amyloid protein precursor (APP) 3) or a-synuclein transgenic mice, 4) and ischemia 5) or scopolamine 6) -treated animals have been used for research in the pathogenesis and therapy of dementia. However, because most studies focused on deficits of the functions of learning and memory that are the main symptoms of dementia, or because only the abnormalities of learning and memory functions are observed in the most models, information regarding BPSD was few in the animal models. Thus, animal models covering peripheral symptoms like BPSD observed in patients with dementia have little been reported. However, recently, it has been reported that not only impairment of learning and memory but also BPSD-like behaviors such as anxiety, depression, muricide, attacking, and startle responses are observed in thiamine-deficient (TD) rats and mice, 7) i.e., the data about BPSD-like behaviors are more abundant than other dementia models. TD is a critical factor in the etiology of Wernicke-Korsakoff's syndrome, which is characterized by a decrease in thiamine pyrophosphate (biologically active form of thiamine)-dependent enzymes involved in cellular glucose and energy metabolism in the brain.8) Thus, although the pathogenesis (or an induction factor) in each dementia model including TD animals is different, there is a common point that memory dysfunction is observed in each model. Furthermore, similar deficiencies in thiamine pyrophosphate-dependent enzyme activities are reported in postmortem brain tissues of patients with Alzheimer's disease. 9) TD has been also reported to induce selective neuronal loss, 10) cholinergic deficits, 11) and accumulations of the abnormal tau isoforms 12) and APP 13) that are involved in Alzheimer's disease. These findings suggest that TD animals may be a valuable tool for evaluation of pharmacotherapy for BPSD as well as dysfunction ...

Senile dementia of the Alzheimer type and multi-infarct dementia are considered to be major problems of contemporary societies. In traditional Chinese medicine, Polygalae Radix (Japanese name: Onji), the root of Polygala tenuifolia WILLDENOW (Polygalaceae), is prescribed for amnesia, neurasthenia, palpitation, noctural emission and insomnia. 1) According to the Chinese Materia Medica, the root is guessed to have a special effect upon the will and mental powers, improving understanding and strengthening the memory.There have been numerous studies regarding the reputed memory-enhancing potential of the roots of P. tenuifolia. DX-9368, which is composed of four herbs (Panax ginseng, P. tenuifolia, Acorus gramineus and Poria cocos), ameliorated the ethanol-and scopolamine-induced memory impairment in mice.2) It is reported by Yabe et al. that the water extract of this plant up-regulates choline acetyltransferase (ChAT) activity and increases NGF secretion in vitro.3) Recently, Egashira et al. reported that the water extract improved the scopolamine-induced impairment of passive avoidance response and enhanced oxotremorine-induced tremors in mice.4) There are few reports, however, on the active constituents involved in the reputed memory-enhancing potential of the roots of P. tenuifolia, and we therefore studied these cognitive improving constituents. In this paper, we report that tenuifoliside B (1) 5) showed a cerebral protective effect on potassium cyanide (KCN)-induced anoxia and an ameliorative effect on the scopolamine-induced impairment of passive avoidance response in rats.It is well known that a decrease in oxygen supply to the brain (hypoxia) depresses cerebral function in experimental animals and humans 6,7) and that memory and learning are impaired by hypoxia in animals and humans. 8,9) The KCN anoxia model is widely used in preclinical evaluations of drugs for the treatment of cerebrovascular disorders. 6,10,11) Therefore, we used this model in addition to the scopolamine-induced impairment of passive avoidance performance as screening method. MATERIALS AND METHODSExtraction and Fractionation of P. tenuifolia As shown in Fig 1, the dried roots (9.4 kg) of P. tenuifolia from Shanxi Province in China (purchased from Yamamoto Yakuhin Kogyo Co., Ltd., Tokyo) were pulverized and extracted twice with boiling MeOH (50 l) for 2 h. The concentrated MeOH extract (PM) (2.21 kg) was dissolved in H 2 O and successively extracted with ether and n-BuOH. These layers were concentrated to give an ethereal soluble fraction (PE, xanthone-containing fraction) (398 g), an n-BuOH soluble fraction (902 g), and a water soluble fraction (PW) (609 g), respectively. The n-BuOH soluble fraction was chromatographed on silica gel [Kieselgel 60, 230-400 mesh (Merck)] (5 kg) with EtOAc-MeOH (4 : 1) and then with MeOH. Concentration of elutions with EtOAc-MeOH (4 : 1) and MeOH afforded the acylated oligosaccharide-containing fraction (PA) (468 g) and saponin-containing fraction (PS) Research Division, Tsumura & Co.; 3586 Yoshiwara Ami-...

The pseudo-oligosaccharides, validamycins, showed potent inhibitory activity against trehalase of Rhizoctonia solani while no significant inhibition was exhibited against cellulase, pectinase, chitinase, a-amylase, a-and /3-glucosidases.In particular, validoxylamine A strongly inhibited trehalase in a competitive manner with a Ki value of 1.9x 10~9 m. The uptake of the antibiotic into the cell and the amount of the intracellular trehalose were investigated by incubating the washed mycelia of R. solani with validamycins. It was found that validamycin A is transported into the cell and hydrolyzed therein by a /2-glucosidase yielding validoxylamine A with greater inhibitory activity. Also validamycin A containing /3-D-glucosyl residue is more favorably taken up into the cell than validamycin D containing a-D-glucosyl residue or their common aglycone, validoxylamine A. In addition, validamycin A suppressed the in vivo degradation of the intracellular trehalose at very low concentration of 0.1 /^g/ml.