Effect of geranylgeranylaceton on cellular damage induced by proteasome inhibition in cultured spinal neurons.
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.
Department of Neurology, Hokkaido University School of Medicine, Sapporo, Japan. skikuti@med.hokudai.ac.jp
Seiji
S
Kikuchi
Kazuyoshi
K
Shinpo
Masayoshi
M
Takeuchi
Sachiko
S
Tsuji
Ichiro
I
Yabe
Masaaki
M
Niino
Kunio
K
Tashiro
D000111:Acetylcysteine / Q000009:adverse effects / Q000031:analogs & derivatives*; D000818:Animals; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D003546:Cysteine Endopeptidases / Q000378:metabolism*; D015853:Cysteine Proteinase Inhibitors / Q000009:adverse effects; D004224:Diterpenes / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D005978:Glutathione / Q000187:drug effects / Q000378:metabolism; D018840:HSP70 Heat-Shock Proteins / Q000378:metabolism; D015151:Immunoblotting; D007150:Immunohistochemistry; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D009097:Multienzyme Complexes / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D018696:Neuroprotective Agents / Q000494:pharmacology*; D009842:Oligopeptides / Q000009:adverse effects; D046988:Proteasome Endopeptidase Complex; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism; D013116:Spinal Cord / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D013879:Thioredoxins / Q000378:metabolism; D013997:Time Factors
D015853:Cysteine Proteinase Inhibitors; D004224:Diterpenes; D018840:HSP70 Heat-Shock Proteins; D009097:Multienzyme Complexes; D018696:Neuroprotective Agents; D009842:Oligopeptides; D017382:Reactive Oxygen Species; C067713:lactacystin; D013879:Thioredoxins; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex; D005978:Glutathione; C031049:geranylgeranylacetone; D000111:Acetylcysteine; C078846:epoxomicin