| Budget Amount *help |
¥3,300,000 (Direct Cost: ¥3,300,000)
Fiscal Year 2003: ¥1,300,000 (Direct Cost: ¥1,300,000)
Fiscal Year 2002: ¥2,000,000 (Direct Cost: ¥2,000,000)
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| Research Abstract |
We devised an organotypic mouse spinal cord culture, based on the conventional protocols using rat The lumbar spinal cords of the mouse pups at postnatal day 2 were used. Neuroprotective effects of one of the most commonly used anticonvulsants, valproic acid (VPA), against glutamate toxicity, were clearly observed. To test the benefit of VPA in vivo, ALS (Amyotrophic lateral sclerosis) model mice (G93A low copy) were treated with VPA (0.26% w/v) from 45 days of age until endpoint We found that VPA treatment led to significant prolongation of the disease duration (36 days). VPA is considered to show the beneficial effect through upreguration of Bcl2, HSP70, and inhibition of HDAC(histone deacetylase), GSK3 β. VPA has long been used with safety and good tolerance in humans, our findings suggest that a good outcome of VPA clinical trials in ALS patients can be expected. Furthermore, neuroprotective effects of VPA might be beneficial to other neurodegenerative diseases, including Parkinson's disease and Alzheimer's disease.
Hepatoma-derived growth factor (HDGF) is a heparin-binding proliferating factor originally isolated from conditioned medium of the hepatoma-derived cell line HuH-7. HDGF is reported to be widely expressed and act as a growth factor in many kinds of cells. However, it has not been investigated in the nervous system. We revealed that HDGF was expressed mainly in neurons, and localized to the nucleus. HDGF was secreted under physiological conditions, and released extracellularly in necrotic conditions. Furthermore, we showed that exogenously supplied HDGF had a neurotrophic effect, and was able to partially prevent the cell death of neurons in which endogenous HDGF was suppressed. Therefore, we propose that HDGF is a novel type of neurotrophic factor, on account of its localization in the nucleus and its potential to function in an autocrine manner under both physiological and pathological conditions.
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