2000 Fiscal Year Final Research Report Summary
Molecular pathomechanism of amyotrophic lateral sclerosis
| Project/Area Number |
11470145
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| Research Category |
Grant-in-Aid for Scientific Research (B).
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Neurology
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| Research Institution | KYOTO UNIVERSITY |
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Principal Investigator |
SHIMOHAMA Shon Kyoto University, Graduate School of Medicine, Assistant Professor, 医学研究科, 講師 (60235687)
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| Co-Investigator(Kenkyū-buntansha) |
AKAIKE Akinori Kyoto University, Graduate School of Medicine, Professor, 薬学研究科, 教授 (80135558)
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| Project Period (FY) |
1999 – 2000
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| Keywords | Amyotrophic lateral sclerosis (ALS) / motor neuron / cell death / estradiol / cyclic GMP / protection / oxidative stress |
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| Research Abstract |
In the present study, we demonstrated that 17β-estradiol and its biologically inactive stereoisomer, 17α-estradiol, prevented glutamate- and nitric oxide-induced selective motor neuronal death observed in primary cultures of the rat spinal cord. The dose of estradiols required for motor neuron protection was greatly reduced by co-administration with glutathione. The results of this study shows that estradiol protects spinal motor neurons from excitotoxic insults in vitro, and may have application as a treatment for amyotrophic lateral sclerosis (ALS).
We also investigated the effect of cyclic GMP against reactive oxygen species (ROS)-induced toxicity in cultured neurons from embryonic rat spinal cords. Pretreatment with a cGMP analogue for 12-24 hours protected both spinal motor neurons and nonmotor neurons against injury induced by either hydrogen peroxide, or a glutathione depletor, BSO.This protective effect was reversed by coadministration with the cGMP-dependent protein kinase (PKG) inhibitor. Interestingly, when cultures were exposed to BSO for 24 hours to allow irreversible inhibition of glutathione synthesis, 8br-cGMP protected only nonmotor neurons. Our results indicate that cGMP attenuates oxidative injury to cultured spinal neurons, in a mechanism associated with glutathione synthesis.
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