Abstract
Hachimijiogan (HJG) is a traditional herbal medicine that improves anxiety disorders in patients with dementia. In this study, we tested the hypothesis that HJG exerts neurotrophic factor-like effects to ameliorate memory impairment in Alzheimer disease (AD) model rats. First, we describe that HJG acts to induce neurite outgrowth in PC12 cells (a rat pheochromocytoma cell line) like nerve growth factor (NGF) in a concentration-dependent manner (3 μg/ml HJG, p < 0.05; 10–500 μg/ml HJG, p < 0.001). While six herbal constituents of HJG, Rehmannia root, Dioscorea rhizome, Rhizoma Alismatis, Poria sclerotium, Moutan bark, and Cinnamon bark, could induce neurite outgrowth effects, the effect was strongest with HJG (500 μg/ml). Second, we demonstrated that HJG-induced neurite outgrowth was blocked by an inhibitor of cAMP response element binding protein (CREB), KG-501 (10 μM, p < 0.001). Moreover, HJG was observed to induce CREB phosphorylation 20–90 min after treatment (20 min, 2.50 ± 0.58-fold) and CRE-mediated transcription in cultured PC12 cells (500 μg/ml, p < 0.01; 1000 μg/ml, p < 0.001). These results suggest a CREB-dependent mechanism underlies the neurotrophic effects of HJG. Finally, we examined improvements of memory impairment following HJG treatment using a Morris water maze in AD model animals (CI + Aβ rats). Repeated oral administration of HJG improved memory impairment (300 mg/kg, p < 0.05; 1000 mg/kg, p < 0.001) and induced CREB phosphorylation within the hippocampus (1000 mg/kg, p < 0.01). Together, our results suggest that HJG possesses neurotrophic effects similar to those of NGF, and can ameliorate cognitive dysfunction in a rat dementia model via CREB activation. Thus, HJG could potentially be a substitute for neurotrophic factors as a treatment for dementia.
Highlights
There have been global increases in the number of patients with dementia disorders, such as Alzheimer’s disease (AD)
Derived from rat pheochromocytomas, PC12 cells are an in vitro neuronal model characterized by the extension of protrusions and differentiation into sympathetic cells following stimulation with nerve growth factor (NGF) (Figures 1A,B)
By measuring the length and number of neurites, we observed a significant increase in total neurite length as the concentration of HJG increased from 3 to 500 μg/ml compared with the control group (Figure 1D and Supplementary Table S1)
Summary
There have been global increases in the number of patients with dementia disorders, such as AD. As the pathogenesis of dementia has not yet been fully elucidated, radical curative therapies have not been established. Novel dementia drugs that do not adversely affect ADL are required. In the study of neurodegenerative diseases characterized by neuronal cell death (such as AD), the role of neurotrophic factors has recently drawn attention. Neurotrophic factors are substances that promote neuronal survival, differentiation, and regeneration. Various trophic factors have been identified, research has indicated important roles for NGF and BDNF (Obara and Nakahata, 2002)
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