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Effect of geranylgeranylaceton on cellular damage induced by proteasome inhibition in cultured spinal neurons
Author(s) -
Kikuchi Seiji,
Shinpo Kazuyoshi,
Takeuchi Masayoshi,
Tsuji Sachiko,
Yabe Ichiro,
Niino Masaaki,
Tashiro Kunio
Publication year - 2002
Publication title -
journal of neuroscience research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.72
H-Index - 160
eISSN - 1097-4547
pISSN - 0360-4012
DOI - 10.1002/jnr.10298
Subject(s) - neurotoxicity , proteasome , lactacystin , spinal cord , amyotrophic lateral sclerosis , pharmacology , intracellular , chemistry , apoptosis , microbiology and biotechnology , neurodegeneration , glutathione , oxidative stress , proteasome inhibitor , biology , biochemistry , toxicity , neuroscience , medicine , enzyme , disease , organic chemistry
Abstract We investigated the effect of two proteasome inhibitors, lactacystin and epoxomicin, on cultured spinal cord neurons. The incubation of spinal neurons with proteasome inhibitors for 24 hr induced neurotoxicity in a dose‐dependent manner. We found motor neurons to be more vulnerable to proteasome‐induced neurotoxicity than nonmotor neurons. The staining of cell bodies in treated motor neurons was markedly disrupted and showed characteristic granular patterns. Proteasome‐induced neurotoxicity is accompanied by apoptotic nuclear changes, posttranslational modification of the cellular proteins, generation of intracellular free radicals, reduction in the amount of reduced glutathione, and mitochondrial dysfunction. Neurotoxicity was reduced by the administration of low concentrations (1–100 nM) of geranylgeranylacetone (GGA), which is widely used as an antiulcer drug, although higher concentrations of this drug produced neurotoxicity in spinal cord neurons. GGA was found to induce the expression of heat shock protein 70 as well as thioredoxin, which may partly contribute to the protective effect of GGA. These data suggest that the inhibition of proteasome may play a role in the mechanism of neurodegenerative diseases of the spinal cord, such as amyotrophic lateral sclerosis, and that the use of GGA may be effective in the treatment of these conditions. © 2002 Wiley‐Liss, Inc.