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).
The principal active anxiolytic components in Saiboku-to, an Oriental herbal medicine, have been isolated and identified as magnolol (5,5'-di-2-propenyl-1,1'-biphenyl-2,2'-diol) and honokiol (3',5-di-2-propenyl-1,1'-biphenyl-2,4'-diol). Evaluation by means of an elevated plus-maze test showed that honokiol was at least 5000 times more potent than Saiboku-to when mice were treated orally for 7 days.
Honokiol, a neolignane derivative of Magnolia bark, has central depressant action and, at much lower doses, anxiolytic activity. We have investigated the characteristics of the behavioural effects of honokiol by means of an elevated plus-maze test. In the plus-maze test a single oral dose of 20 mg kg(-1) honokiol significantly prolonged the time spent in the open arms of the maze, suggesting anxiolytic effect. Moreover, when honokiol was administered daily for seven days and the plus-maze test was conducted 3 or 24 h after the last administration, significant prolongation of the time in the open arms was manifested even for doses of 0.2 mg kg(-1). The maximum effect was observed for doses of 0.5 mg kg(-1). Honokiol at any dose in both single and repeated administration schedules caused neither change in motor activity nor disruption of traction performance. Orally administered diazepam, 0.5-2 mg kg(-1), caused dose-dependent prolongation of the time spent in the open arms of the maze with a significant increase in motor activity at 1 mg kg(-1), and dose-dependent disruption of traction performance. The changes in the plus-maze performance after treatment for seven days with 0.2 mg kg(-1) honokiol and after a single treatment with 1 mg kg(-1) diazepam were almost equivalent. The effect of honokiol (0.2 mg kg(-1), treatment for seven days) was inhibited by subcutaneous flumazenil (0.3 mg kg(-1)) and (+)-bicuculline (0.1 mg kg(-1)) and by intraperitoneal CCK-4 (50 microg kg(-1)) and caffeine (30 mg kg(-1)). The anxiolytic effect of diazepam (1 mg kg(-1)) was also inhibited by flumazenil and bicuculline. However, the combined administration of diazepam with caffeine enhanced the effect, and diazepam completely reversed the effect of CCK-4. These results suggest that, in contrast with diazepam, honokiol selectively induces an anxiolytic effect with less liability of eliciting motor dysfunction and sedation or disinhibition. The combined effects of the drug also revealed that the mechanism of anxiolytic effect of honokiol is partially different from that of diazepam.
Abstract-Effectsof central depressants-chlorpromazine, diazepam, pentobarbital and ethanol-on rota-rod and traction performances in mice were investigated. The walking technique of the animals on the rotating rod (3 cm in diameter, 24 r. p. m.) was established after about 15 trials, and was well maintained for one week thereafter. No training was required for the traction.Both the rota-rod and traction performances were inhibited by chlorpromazine, diazepam, pentobarbital and ethanol in fairly good parallel with the dosages. However, the sensitivities to one same drug markedly differed between the two performances.Chlorpromazine more than diazepam inhibited the rota-rod, while in the traction performance the inhibition with diazepam was greater than that with chlorpromazine.Pentobarbital and ethanol inhibited the two perfor mances to nearly the same degree. On the basis of the present results, the rota-rod test is considered to be suitable for the estimation of the positive adaptability to forced motor activity, and the traction for that of muscle relaxation.By comparing the dose effect relationships in the two performances, it may be possible to elucidate the character istics of various central depressants, and to apply these procedures for the screening test in drug evaluations.When a mouse is repeatedly placed on a rod or cylinder which is rotating at a constant speed, the animal gradually learns to walk on it, adapting itself to the rotation speed. After ingestion of a central depressant, however, the animal easily falls from the rod. This procedure is called 'rota-rod test' and was first introduced by Dunham and Miya (1) for assaying the drug effects on the motor activity. Since then, the effects of various central depressants, investigated by this test have been reported (2-4). There is, however, no established interpretation of the results obtained by this test, for many factors, e.g. lowered general activity, ataxia, muscle relaxation, fatigue, etc, are considered to inhibit the rota-rod performance (RR performance).On the other hand, when a mouse hangs from a thin bar by means of its forelimbs, the animal can maintain this posture for a certain time without falling. This traction behavior (TR performance) or grasping reflex is also sharply altered by central depressants.We studied the effects of various central depressants on these two performances, and found that the sensitivities differed depending on the drug. MATERIALS AND METHODSAdult, male ddG strain mice were obtained from the breeding room of Gunma Univer sity, Medical School. A solid diet MF (Oriental Yeast Co., Tokyo) and tap water were
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