The neuroprotective effects of GTS-21 [3-(2,4-dimethoxybenzylidene)-anabaseine dihydrochloride] were studied and compared with those of nicotine, 9-amino-1,2,3,4-tetrahydroacridine hydrochloride hydrate (THA) and pentobarbital-Na (PB) using a cerebral ischemia model in Mongolian gerbils. The learning performance and memory retention were elucidated by a step-through passive avoidance task at 2 and 3 days after ischemia-reperfusion. In this task, the ischemia-operated gerbils showed impairment of learning performance and memory retention. Neuronal cell death in the hippocampal CA1 area was observed at 7 days after ischemia. When administered i.p. 30 min before ischemia, GTS-21 (5 mg/kg), (-)-nicotine (1.5 mg/kg), THA (5 mg/kg) and PB (50 mg/kg) significantly attenuated the impairment of passive avoidance performance and the neuronal cell death induced by the ischemia. When administered orally twice daily for 2 weeks prior to the ischemia, GTS-21 (10 mg/kg) significantly suppressed both amnesia and neuronal cell death, while (-)-nicotine (10 mg/kg) and THA (10 mg/kg) suppressed only the amnesia. These results suggest that GTS-21 exerts a protective activity on not only impairment of learning and memory but also delayed neuronal death and that the underlying mechanism of GTS-21 differs from that of nicotine or THA.
Cortical and hippocampal EEGs in animal models of schizophrenia were compared to those obtained with psychotomimetics or antipsychotic agents by utilizing power spectral analysis. Models of positive schizophrenic symptoms were created with methamphetamine (MAP) and cocaine, and a model of both negative and positive symptoms was created with PCP. MAP caused a prolonged decrease in the cortical EEG power spectra, cocaine caused a marked decrease for a short time, and PCP produced no significant changes. In the hippocampal spectra, MAP induced a marked increase in the T2(6.0-7.9 Hz)/ T1(4.0-5.9 Hz) ratio, PCP caused a decrease of this ratio after an initial increase, and cocaine produced no significant change. (An increase in the T2/T1 ratio represents a shift of theta waves to higher frequencies.) Since apomorphine (a DA agonist) and MK-801 (an NMDA antagonist) caused the T2/T1 ratio to increase, positive schizophrenic symptoms caused by MAP may be related to the DA and NMDA systems. 3-PPP (a sigma agonist) caused biphasic changes similar to those induced by PCP. Haloperidol and chlorpromazine caused a decrease of the T2/T1 ratio. These results indicate that cortical and hippocampal EEG power spectra (especially the hippocampal T2/T1 ratio) can be used to characterize both qualitatively and quantitatively models of schizophrenia.
The triple therapy including lafutidine is equivalent to triple therapy including lansoprazole in terms of H pylori eradication rates and improvement in gastroesophageal reflux and abdominal symptoms. These results are attributed to the fact that lafutidine has strong, continuous antisecretory activity, unaffected by CYP2C19 polymorphisms.
ABSTRACT-Effect of subchronically administered GTS-21 [3-(2,4-dimethoxybenzylidene)-anabaseine di hydrochloride], a selective nicotinic agonist, on neuronal cell loss caused by nucleus basalis magnocellularis (nBM) lesion was studied in rats. After 2 weeks of bilateral nBM excitotoxic lesion, GTS-21 was orally administered once daily for 20 weeks. Neuronal cell loss was observed in layers 11-111 of the parietal cortex in the lesioned control rats. GTS-21 significantly attenuated the neuron loss in these layers. These results suggest that GTS-21 exhibits a protective action against the neuronal cell death in the parietal cortex and may have a beneficial effect on neurodegenerative disorders such as an Alzheimer-type disease. (1) have found neuronal cell loss and cytopathological abnormalities in the nucleus basalis magnocellularis (nBM) in AD patients. These authors also have demonstrated a strong correlation be tween the frequency of neuritic plaques in the cerebral cortex and the neuronal loss in the nBM. Moreover, the decrease of nicotinic receptors in the frontal cortex has been shown in AD patients (2). These findings suggest that the nicotinic receptor system plays an important role in cognitive and neurophysiological function.The recent report by Newhouse et al. (3) has demon strated that the intravenous administration of nicotine partially improves cognitive performance in AD patients, suggesting the role of central nicotinic acetylcholine receptors in cognitive and pathophysiological changes in AD. Moreover, their findings give rise to the possibility that stimulation of the remaining nicotinic receptors can alleviate the cognitive deficits induced by dysfunction of central cholinergic systems.GTS-21 [3-(2,4-dimethoxybenzylidene)-anabaseine di hydrochloride], a selective nicotinic agonist, reportedly improves the learning performance in nucleus basalis lesioned rats (4). Moreover, a recent study indicates that nicotinic drugs exert a protective activity against fimbrial transection-induced neuronal cell loss when administered systemically 1 hr before and every 12 hr after the transec tion (5).In rodents, an injection of ibotenic acid, an excitotox in, into the nBM causes a decrease in the number of neuro nal cells in the cerebral cortex and attenuates the cortical cholinergic activities in rats (6, 7). This nBM lesion is also known to impair memory-related behaviors. Thus, the nBM-lesioned rats provide an animal model with brain dysfunction similar to that observed in AD and have been used to elucidate the therapeutic potential of drugs in AD patients.In the present study, to elucidate this possibility, we examined whether per orally administered GTS-21 exerts a protective action against neocortical neuronal cell loss caused by bilateral nBM-lesion in rats.Male Wistar rats (8-weeks-old; Clea Japan, Inc., Tokyo) were housed 3 4 per cage at least for 1 week be fore the start of the experiments. The housing was thermo statically maintained at 21 卤 1 C with a constant humidity (45-6507o) and a 12-hr light-da...
The hippocampal EEG power spectra of rabbits were analyzed to clarify the relationship between the theta-wave and emotionality. The relative power of T2 (6.0-7.9 Hz)/T1 (4.0-5.9 Hz) represented the index of theta-wave change. Emotional excitement (produced with novelty stress or methamphetamine) or suppression (produced with restraint stress or reserpine) increased or decreased T2/T1 ratios within around +/- 1 Hz changes. Furthermore, the imaging patterns of the peak feature make possible detailed characterization of emotional states. These results suggest that the hippocampus finely adjusts the theta-wave on a +/- 1 Hz level, with a fine balance of voltage, in response to the emotional activity.
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