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.
We examined the effects of GTS-21 [3-(2,4-dimethoxybenzylidene)-anabaseine dihydrochloride], a nicotinic agonist, on histopathological changes of the brain and radial maze learning performance in rats with permanent occlusion of the bilateral common carotid arteries (2VO) and elucidated whether this compound has a protective effect against the neuronal degeneration and spatial cognitive deficit caused by chronic ischemia. Rats were administered GTS-21 (1 and 10 mg/kg, p.o.) or vehicle 24 hr and 30 min before the 2VO operation and then once daily for 2 months after the operation. The 2VO rats given vehicle had multiple infarctions in the cerebral cortex, hippocampus and striatum and rarefaction in the white matter at 2 months after the operation, although the number and distribution of infarctions varied among individual animals. In addition, the 2VO rats given vehicle showed a higher rate of errors in the acquisition trials of the 8-arm radial maze task than sham-operated controls. However, 2VO rats treated with GTS-21 (1 and 10 mg/kg, p.o.) showed significantly decreased neuropathological changes and less errors in the acquisition trials compared to the vehicle-treated 2VO rats. These results indicate that GTS-21 attenuates impairment of spatial cognitive deficit and progressive neuronal degeneration induced by 2VO and suggest that this compound is beneficial for the treatment of neurodegenerative diseases following chronic cerebral hypoperfusion.
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 ± 1 C with a constant humidity (45-6507o) and a 12-hr light-da...
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.