Ginkgo biloba extract EGb 761 attenuates hippocampal neuronal loss and cognitive dysfunction resulting from chronic restraint stress in ovariectomized rats
Laboratory of Neuropsychopharmacology, Graduate School of Natural Science and Technology, Kanazawa University, Kakuma-machi, Kanazawa 920-1192, Japan. Neuroscience
(Impact Factor: 3.36).
11/2007; 149(2):256-62. DOI: 10.1016/j.neuroscience.2007.07.042
We have recently found that a combination of ovariectomy (OVX) and chronic restraint stress causes cognitive dysfunction and reduces hippocampal CA3 neurons in female rats and that estrogen replacement suppresses the OVX/stress-induced behavioral and morphological changes. In this study, we examined the effect of Ginkgo biloba extract (EGb 761), a popular herbal supplement, on the cognitive dysfunction and neuromorphological change in OVX/stress-subjected rats. Female Fisher 344 rats were randomly divided into three groups: vehicle-treated OVX, EGb 761 (50 mg/kg) -treated OVX and vehicle-treated sham-operated control groups. Two months after ovariectomy, all animals received restraint stress for 21 days (6 h/day), and were then subjected to a novel object recognition test followed by morphological examination by Nissl staining. EGb 761 was orally administered once daily until the behavioral analysis was done. Treatment with EGb 761 improved memory impairment and neuronal loss of hippocampus in the OVX/stress-subjected group in the same ways as 17beta-estradiol. On the other hand, EGb 761 did not affect the loss of bone mineral density and increase in body weight after OVX, although 17beta-estradiol attenuated them. These results have important implications for neuroprotective and cognition enhancing effects of EGb 761 in postmenopausal women and suggest that the effects are mediated by a different mechanism from estrogen.
Available from: Hideyuki Takeuchi
- "oA␤ induces neuronal oxidative stress by activating N-methyl-daspartate (NMDA) receptors, leading to neuronal death . We also have demonstrated that the intracerebroventricular (i.c.v.) injection of A␤ induces cognitive deficits  as well as impairment of the cholinergic system and down-regulation of brain-derived neurotrophic factor (BDNF); these changes play important roles in cognitive and morphological deficits associated with aging and neurodegenerative diseases  . Fingolimod is an oral immunosuppressant, which has been recently approved for treatment of multiple sclerosis    . "
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ABSTRACT: Alzheimer's disease is a progressive neurodegenerative disorder. Amyloid β, a neurotoxic protein, causes disruption of hippocampal synaptic plasticity, and induces cognitive impairment in Alzheimer's disease. We previously revealed that fingolimod, a new oral immunosuppressant used to treat multiple sclerosis, ameliorates oligomeric amyloid β-induced neuronal damage via up-regulation of neuronal brain-derived neurotrophic factor (BDNF). Here, we showed that oral administration of fingolimod ameliorated the impairment in object recognition memory and associative learning in mice injected with amyloid β. This effect was associated with restoration of normal BDNF expression levels in the cerebral cortices and hippocampi, suggesting that neuroprotection was mediated by up-regulation of neuronal BDNF levels. Therefore, fingolimod may provide therapeutic effects in patients with Alzheimer's disease.
Available from: Taku Nagai
- "Restraint stress ICR mice were randomly divided into two groups: a restraint-stress group and a control group. Restraint stress was applied with a stainless mesh that allowed for a close fit to the mice for 3 h, as described previously (Takuma et al. 2007; Yun et al. 2010). Mifepristone, a GR antagonist (Sigma-Aldrich, St Louis, MO, USA), was injected i.p. at a dose of 25 mg/kg, 30 min before exposure to restraint stress. "
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ABSTRACT: Neuronal PAS domain 4 (NPAS4), a brain-specific helix-loop-helix transcription factor, has recently been shown to regulate the development of GABAergic inhibitory neurons. We previously reported that Npas4 mRNA expression levels were reduced in the hippocampus of mice exposed to social isolation or restraint stress, which was accompanied by impairment of memory, emotional behavior, and hippocampal neurogenesis. Therefore, the reduction of NPAS4 expression may play a role in stress-induced brain dysfunction. In this study, to investigate the transcriptional regulation of Npas4 by stress, we focused on the effect of glucocorticoids (GCs) upon Npas4 transcription. Corticosterone treatment reduced Npas4 expression in the frontal cortex and hippocampus, whereas adrenalectomy caused an increase in expression. GC receptor (GR) antagonist, mifepristone, inhibited the stress-induced reduction of Npas4 expression. Putative negative glucocorticoid response elements (GREs) were found -2000 to -1000 upstream of the Npas4 transcription initiation site. Npas4 promoter activity was increased by mifepristone or by mutation of the negative GRE sequences. A chromatin immunoprecipitation assay revealed that restraint stress increased the binding of GR to Npas4 promoter region in the hippocampus. These results suggest that transcription of Npas4 is down-regulated by stress via the binding of agonist-bound GR to its promoter.
Available from: Mehrdad Jahanshahi
- "Takuma et al.  examined the effect of G. biloba extract (EGb 761) on cognitive dysfunction and neuromorphological change in ovariectomised (OVX)/stress subjected rats. Their results showed that treatment with EGb 761 improved memory impairment and neuronal loss of the hippocampus in the OVX/stress-subjected group in the same ways as 17-β-estradiol. "
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ABSTRACT: The regular extract of Ginkgo biloba has been shown to possess neuroprotective properties in disorders like hypoxia, ischemia, seizure activity and peripheral nerve damage. Also, G. biloba has received attention as a potential cognitive enhancer for the treatment of Alzheimer's disease, but there is not any documentation about the effect of an extract of G. biloba on astrocytes. Therefore, the aim of this study was examined the effects of G. biloba extract on the rat's hippocampal astrocytes after scopolamine based amnesia. In this study, 36 adult male Wistar rats were used. Rats were randomly distributed into control, sham, protective and treatment groups. The rats in the sham group only received scopolamine hydrobromide (3 mg/kg) intraperitoneally. The rats in the protective and treatment groups received G. biloba extract (40, 80 mg/kg) for 7 days intraperitoneally before and after scopolamine injection. Forty eight hours after the last injection, the brains of the rats were withdrawn and fixed with paraformaldehide, and then after histological processing, the slices were stained with phosphotungstic acid-haematoxylin for astrocytes. Data were analyzed by the analysis of variance (ANOVA) post hoc Tukey test; P<0.05 was considered significant. Results showed that scopolamine can reduce the number of astrocytes in all areas of hippocampal formation compared with the control. However, G. biloba extract can compensate for the reduction in the number of astrocytes in the hippocampus before or after the encounter with scopolamine. We concluded that a pretreatment and treatment injection of G. biloba extract can have a protective effect for astrocytes in all areas of hippocampal formation.
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