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Missense mutations of the tau gene cause autosomal dominant frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17), an illness characterized by progressive personality changes, dementia, and parkinsonism. There is prominent frontotemporal lobe atrophy of the brain accompanied by abundant tau accumulation with neurofibrillary tangles and neuronal cell loss. Using a hamster prion protein gene expression vector, we generated several independent lines of transgenic (Tg) mice expressing the longest form of the human four-repeat tau with the R406W mutation associated with FTDP-17. The TgTauR406W 21807 line showed tau accumulation beginning in the hippocampus and amygdala at 6 months of age, which subsequently spread to the cortices and subcortical areas. The accumulated tau was phosphorylated, ubiquitinated, conformationally changed, argyrophilic, and sarcosyl-insoluble. Activation of GSK-3beta and astrocytic induction of mouse tau were observed. Astrogliosis and microgliosis correlated with prominent tau accumulation. Electron microscopic examination revealed the presence of straight filaments. Behavioral tests showed motor disturbances and progressive acquired memory loss between 10 to 12 months of age. These findings suggested that TgTauR406W mice would be a useful model in the study of frontotemporal dementia and other tauopathies such as Alzheimer's disease (AD).

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 ...

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Dementia is a progressive neurodegenerative disorder with cognitive dysfunction, and is often complicated by behavioral and psychological symptoms of dementia (BPSD) including excitement, aggression, and hallucinations. Typical and atypical antipsychotics are used for the treatment of BPSD, but induce adverse events. The traditional Japanese Kampo medicine yokukansan (YKS), which had been originated from the traditional Chinese medicine Yi-Gan-San, has been reported to improve BPSD without severe adverse effects. In the preclinical basic studies, there are over 70 research articles indicating the neuropharmacological efficacies of YKS. In this review, we first describe the neuropharmacological actions of YKS and its bioactive ingredients. Multiple potential actions for YKS were identified, which include effects on serotonergic, glutamatergic, cholinergic, dopaminergic, adrenergic, and GABAergic neurotransmissions as well as neuroprotection, anti-stress effect, promotion of neuroplasticity, and anti-inflammatory effect. Geissoschizine methyl ether (GM) in Uncaria hook and 18β-glycyrrhetinic acid (GA) in Glycyrrhiza were responsible for several pharmacological actions of YKS. Subsequently, we describe the pharmacokinetics of GM and GA in rats. These ingredients were absorbed into the blood, crossed the blood-brain barrier, and reached the brain, in rats orally administered YKS. Moreover, autoradiography showed that [(3)H]GM predominantly distributed in the frontal cortex and [(3)H]GA in the hippocampus. Thus, YKS is a versatile herbal remedy with a variety of neuropharmacological effects, and may operate as a multicomponent drug including various active ingredients.

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Effects of a traditional Japanese medicine, yokukansan, which is composed of seven medicinal herbs, on glutamate-induced cell death were examined using primary cultured rat cortical neurons. Yokukansan (10-300 μg/ml) inhibited the 100 μM glutamate-induced neuronal death in a concentration-dependent manner. Among seven constituent herbs, higher potency of protection was found in Uncaria thorn (UT) and Glycyrrhiza root (GR). A similar neuroprotective effect was found in four components (geissoschizine methyl ether, hirsuteine, hirsutine, and rhynchophylline) in UT and four components (glycycoumarin, isoliquiritigenin, liquiritin, and 18β-glycyrrhetinic acid) in GR. In the NMDA receptor binding and receptor-linked Ca(2+) influx assays, only isoliquiritigenin bound to NMDA receptors and inhibited the glutamate-induced increase in Ca(2+) influx. Glycycoumarin and 18β-glycyrrhetinic acid bound to NMDA receptors, but did not inhibit the Ca(2+) influx. The four UT-derived components did not bind to NMDA receptors. The present results suggest that neuroprotective components (isoliquiritigenin, glycycoumarin, liquiritin, and 18β-glycyrrhetinic acid in GR and geissoschizine methyl ether, hirsuteine, hirsutine, and rhynchophylline in UT) are contained in yokukansan, and isoliquiritigenin, which is one of them, is a novel NMDA receptor antagonist.

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